15-92967373-A-G

Variant names:

• chr15-92967373-A-G
• rs4777755
• NM_001271.4:c.2049A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001271.4(CHD2):​c.2049A>G​(p.Glu683Glu) 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
• Publications: 21 publications found

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]

CHD2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 94

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	NM_001271.4	MANE Select	c.2049A>G	p.Glu683Glu	synonymous	Exon 17 of 39	NP_001262.3	O14647-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.2049A>G	p.Glu683Glu	synonymous	Exon 17 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.2049A>G	p.Glu683Glu	synonymous	Exon 17 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000628118.2	TSL:1	n.996A>G		non_coding_transcript_exon	Exon 8 of 23	ENSP00000515059.1	A0A8V8TRB2

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

GnomAD2 exomes AF: 0.850 AC: 212954 AN: 250602 AF XY: 0.854

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 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

African (AFR) AF: 0.619 AC: 20652 AN: 33386

American (AMR) AF: 0.916 AC: 40908 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23659 AN: 26082

East Asian (EAS) AF: 0.998 AC: 39585 AN: 39648

South Asian (SAS) AF: 0.900 AC: 77495 AN: 86142

European-Finnish (FIN) AF: 0.760 AC: 40575 AN: 53386

Middle Eastern (MID) AF: 0.922 AC: 5305 AN: 5756

European-Non Finnish (NFE) AF: 0.839 AC: 931382 AN: 1110256

Other (OTH) AF: 0.843 AC: 50838 AN: 60284

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

African (AFR) AF: 0.613 AC: 25354 AN: 41346

American (AMR) AF: 0.887 AC: 13520 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3150 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5158 AN: 5170

South Asian (SAS) AF: 0.909 AC: 4371 AN: 4810

European-Finnish (FIN) AF: 0.755 AC: 7976 AN: 10568

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56681 AN: 67956

Other (OTH) AF: 0.826 AC: 1741 AN: 2108

Alfa AF: 0.823 Hom.: 149628

Bravo AF: 0.788

Asia WGS AF: 0.934 AC: 3249 AN: 3478

EpiCase AF: 0.854

EpiControl AF: 0.857

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Developmental and epileptic encephalopathy 94 (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.4
DANN	Benign	0.63
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4777755; hg19: chr15-93510603; COSMIC: COSV108240537; COSMIC: COSV108240537;