chr15-92974957-T-C

Position:

• chr15-92974957-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001271.4(CHD2):​c.2577+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,612,200 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: CHD2 NM_001271.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001672
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.62

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-92974957-T-C is Benign according to our data. Variant chr15-92974957-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-92974957-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.2577+7T>C		splice_region_variant, intron_variant		ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.2577+7T>C		splice_region_variant, intron_variant		5	NM_001271.4	ENSP00000377747.4

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00354 AC: 883 AN: 249424 Hom.: 4 AF XY: 0.00372 AC XY: 502 AN XY: 134830

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00511 AC: 7459 AN: 1459874 Hom.: 27 Cov.: 29 AF XY: 0.00508 AC XY: 3687 AN XY: 726322

Gnomad4 AFR exome AF: 0.000778

Gnomad4 AMR exome AF: 0.00296

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00309

Gnomad4 NFE exome AF: 0.00608

Gnomad4 OTH exome AF: 0.00403

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74500

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00564

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CHD2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 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	PreventionGenetics, part of Exact Sciences	-	- -

Developmental and epileptic encephalopathy 94 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.5
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.014

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

Publications

LitVar

Other links and lift over

dbSNP: rs146944583; hg19: chr15-93518187; COSMIC: COSV104431366; COSMIC: COSV104431366;