chr15-92967373-A-G

Position:

• chr15-92967373-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001271.4(CHD2):​c.2049A>G​(p.Glu683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,611,470 control chromosomes in the GnomAD database, including 568,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47698 hom., cov: 29)
  • Exomes 𝑓: 0.84 (520823 hom.)
• Consequence: CHD2 NM_001271.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.420

Genes affected

CHD2 (HGNC:1917): (chromodomain helicase DNA binding protein 2) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-92967373-A-G is Benign according to our data. Variant chr15-92967373-A-G is described in ClinVar as [Benign]. Clinvar id is 257706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-92967373-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.2049A>G	p.Glu683=	synonymous_variant	17/39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.2049A>G	p.Glu683=	synonymous_variant	17/39	5	NM_001271.4	ENSP00000377747	P1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 118976 AN: 151760 Hom.: 47659 Cov.: 29

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.935

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.825

GnomAD3 exomes AF: 0.850 AC: 212954 AN: 250602 Hom.: 91496 AF XY: 0.854 AC XY: 115718 AN XY: 135476

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.922

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.901

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.843 AC: 1230399 AN: 1459588 Hom.: 520823 Cov.: 37 AF XY: 0.845 AC XY: 613480 AN XY: 726182

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.916

Gnomad4 ASJ exome AF: 0.907

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.900

Gnomad4 FIN exome AF: 0.760

Gnomad4 NFE exome AF: 0.839

Gnomad4 OTH exome AF: 0.843

GnomAD4 genome AF: 0.784 AC: 119069 AN: 151882 Hom.: 47698 Cov.: 29 AF XY: 0.789 AC XY: 58555 AN XY: 74260

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.887

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.909

Gnomad4 FIN AF: 0.755

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.826

Alfa AF: 0.837 Hom.: 105741

Bravo AF: 0.788

Asia WGS AF: 0.934 AC: 3249 AN: 3478

EpiCase AF: 0.854

EpiControl AF: 0.857

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy 94 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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	-0.55
CADD	Benign	7.4
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4777755; hg19: chr15-93510603;