NM_001170629.2(CHD8):c.6295G>A (p.Glu2099Lys) AND Intellectual developmental disorder with autism and macrocephaly

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 26, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000678363.2

Allele description [Variation Report for NM_001170629.2(CHD8):c.6295G>A (p.Glu2099Lys)]

NM_001170629.2(CHD8):c.6295G>A (p.Glu2099Lys)

Gene:

CHD8:chromodomain helicase DNA binding protein 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_001170629.2(CHD8):c.6295G>A (p.Glu2099Lys)

HGVS:

NC_000014.9:g.21393500C>T
NG_021249.1:g.48799G>A
NM_001170629.2:c.6295G>AMANE SELECT
NM_020920.4:c.5458G>A
NP_001164100.1:p.Glu2099Lys
NP_001164100.1:p.Glu2099Lys
NP_065971.2:p.Glu1820Lys
NC_000014.8:g.21861659C>T
NM_001170629.1:c.6295G>A

Protein change:

E1820K

Links:

dbSNP: rs1555313219

NCBI 1000 Genomes Browser:

rs1555313219

Molecular consequence:

NM_001170629.2:c.6295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020920.4:c.5458G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Intellectual developmental disorder with autism and macrocephaly
Synonyms:: Autism, susceptibility to, 18
Identifiers:: MONDO: MONDO:0014017; MedGen: C3554373; OMIM: 615032

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000804429	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 26, 2017)	de novo	provider interpretation, clinical testing	PubMed (5) [See all records that cite these PMIDs] 22495309, 23160955, 24998929, 26789910, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000804429

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 26, 2017)

de novo

provider interpretation, clinical testing

PubMed (5)
[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	de novo	yes	1	not provided	not provided	1	not provided	clinical testing, provider interpretation

Citations

PubMed

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.

O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, et al.

Nature. 2012 Apr 4;485(7397):246-50. doi: 10.1038/nature10989.

PubMed [citation]

PMID:: 22495309
PMCID:: PMC3350576

Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.

O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, et al.

Science. 2012 Dec 21;338(6114):1619-22. doi: 10.1126/science.1227764. Epub 2012 Nov 15.

PubMed [citation]

PMID:: 23160955
PMCID:: PMC3528801

See all PubMed Citations (5)

Details of each submission

From Geisinger Autism and Developmental Medicine Institute, Geisinger Health System, SCV000804429.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	PubMed (5)
2	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

This 12 year old male with moderate intellectual disability was found to carry a de novo variant in CHD8. In-silico splice prediction models predict that c.6295G>A may create or enhance a cryptic splice donor site in exon 31 that could supplant the natural splice donor site. However, in the absence of RNA/functional studies, the actual effect of the c.6295G>A change in this individual is unknown. If c.6295G>A does not alter splicing, it will result in the E2099K missense change. The E2099K variant is a non-conservative amino acid substitution, and computational prediction models are inconsistent. The variant is absent from population databases and has not been previously reported in any individuals with CHD8-Related Disorder, to our knowledge.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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