NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter) AND Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 9, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000779470.10

Allele description [Variation Report for NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter)]

NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter)

Gene:

IL12B:interleukin 12B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q33.3

Genomic location:

Preferred name:

NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter)

HGVS:

NC_000005.10:g.159320343A>T
NG_009618.1:g.15131T>A
NM_002187.3:c.660T>AMANE SELECT
NP_002178.2:p.Tyr220Ter
NP_002178.2:p.Tyr220Ter
LRG_71t1:c.660T>A
LRG_71:g.15131T>A
LRG_71p1:p.Tyr220Ter
NC_000005.9:g.158747351A>T
NM_002187.2:c.660T>A

Protein change:

Y220*

Links:

dbSNP: rs748215576

NCBI 1000 Genomes Browser:

rs748215576

Molecular consequence:

NM_002187.3:c.660T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
Synonyms:: IL12B DEFICIENCY; Immunodeficiency 29
Identifiers:: MONDO: MONDO:0013954; MedGen: C4013948; Orphanet: 319558; OMIM: 614890

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Homo sapiens PIN2 (TERF1) interacting telomerase inhibitor 1 (PINX1), transcript...
Homo sapiens PIN2 (TERF1) interacting telomerase inhibitor 1 (PINX1), transcript variant 2, mRNA
gi|1890328987|ref|NM_001284356.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916098	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Aug 23, 2017)	germline	clinical testing	Citation Link,
SCV003457279	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11753820, 23429356, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916098

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Aug 23, 2017)

germline

clinical testing

Citation Link,

SCV003457279

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 9, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds.

Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Génin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, et al.

Am J Hum Genet. 2002 Feb;70(2):336-48. Epub 2001 Dec 17.

PubMed [citation]

PMID:: 11753820
PMCID:: PMC384913

Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Al-Mousa H, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, et al.

Medicine (Baltimore). 2013 Mar;92(2):109-122. doi: 10.1097/MD.0b013e31828a01f9. Erratum in: Medicine (Baltimore). 2013 May;92(3):190. Alangari, Abdullah A [added]; Mobaireek, Khalid F [added].

PubMed [citation]

PMID:: 23429356
PMCID:: PMC3822760

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916098.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The IL12B c.660T>A (p.Tyr220Ter) variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive familial atypical mycobacteriosis.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003457279.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 632459). This sequence change creates a premature translational stop signal (p.Tyr220*) in the IL12B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL12B are known to be pathogenic (PMID: 11753820, 23429356). This variant is present in population databases (rs748215576, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with IL12B-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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