rs182330071

chr15-93002171-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.4138-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,580,670 control chromosomes in the GnomAD database, including 2 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 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: CHD2 NM_001271.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001476
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.38

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-93002171-T-C is Benign according to our data. Variant chr15-93002171-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 384175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-93002171-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.4138-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394196.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.4138-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001271.4	P1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000928 AC: 200 AN: 215544 Hom.: 1 AF XY: 0.000664 AC XY: 78 AN XY: 117486

Gnomad AFR exome AF: 0.00994

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000787

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000348 AC: 497 AN: 1428622 Hom.: 2 Cov.: 31 AF XY: 0.000321 AC XY: 228 AN XY: 710438

Gnomad4 AFR exome AF: 0.00923

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000936

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000707

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00308 AC: 468 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.00314 AC XY: 233 AN XY: 74306

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.00368

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CHD2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 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. -

CHD2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy 94 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0060

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

Publications

LitVar

Other links and lift over

dbSNP: rs182330071; hg19: chr15-93545401;