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14-21385739-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001170629.2(CHD8):c.7620C>T(p.Asp2540=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,551,282 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

CHD8
NM_001170629.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.651
Variant links:
Genes affected
CHD8 (HGNC:20153): (chromodomain helicase DNA binding protein 8) This gene encodes a member of the chromodomain-helicase-DNA binding protein family, which is characterized by a SNF2-like domain and two chromatin organization modifier domains. The encoded protein also contains brahma and kismet domains, which are common to the subfamily of chromodomain-helicase-DNA binding proteins to which this protein belongs. This gene has been shown to function in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Allelic variants of this gene are associated with autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-21385739-G-A is Benign according to our data. Variant chr14-21385739-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.651 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000521 (79/151732) while in subpopulation NFE AF= 0.000633 (43/67934). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHD8NM_001170629.2 linkuse as main transcriptc.7620C>T p.Asp2540= synonymous_variant 38/38 ENST00000646647.2
LOC107984643XR_001750627.2 linkuse as main transcriptn.441+1026G>A intron_variant, non_coding_transcript_variant
CHD8NM_020920.4 linkuse as main transcriptc.6783C>T p.Asp2261= synonymous_variant 38/38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHD8ENST00000646647.2 linkuse as main transcriptc.7620C>T p.Asp2540= synonymous_variant 38/38 NM_001170629.2 P3Q9HCK8-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000521
AC:
79
AN:
151618
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000970
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.000461
Gnomad ASJ
AF:
0.00519
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000623
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000633
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000895
AC:
141
AN:
157494
Hom.:
0
AF XY:
0.000950
AC XY:
79
AN XY:
83158
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000729
Gnomad ASJ exome
AF:
0.00504
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000922
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000849
Gnomad OTH exome
AF:
0.00158
GnomAD4 exome
AF:
0.000653
AC:
914
AN:
1399550
Hom.:
2
Cov.:
35
AF XY:
0.000663
AC XY:
458
AN XY:
690284
show subpopulations
Gnomad4 AFR exome
AF:
0.0000633
Gnomad4 AMR exome
AF:
0.000756
Gnomad4 ASJ exome
AF:
0.00417
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000997
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000575
Gnomad4 OTH exome
AF:
0.00122
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000521
AC:
79
AN:
151732
Hom.:
0
Cov.:
30
AF XY:
0.000526
AC XY:
39
AN XY:
74144
show subpopulations
Gnomad4 AFR
AF:
0.0000967
Gnomad4 AMR
AF:
0.000461
Gnomad4 ASJ
AF:
0.00519
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000633
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000792
Hom.:
0
Bravo
AF:
0.000582
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxJan 24, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 28, 2015- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022CHD8: BS1, BS2 -
Benign, criteria provided, single submitterclinical testingInvitaeJan 13, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2017This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
3.4
Dann
Benign
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs367905297; hg19: chr14-21853898; COSMIC: COSV53523097; COSMIC: COSV53523097; API