rs139534358

Positions:

• chr15-93020154-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001271.4(CHD2):​c.5049C>T​(p.Ala1683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: CHD2 NM_001271.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0310

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 15-93020154-C-T is Benign according to our data. Variant chr15-93020154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-93020154-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.031 with no splicing effect.
• BS2: High AC in GnomAd4 at 185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.5049C>T	p.Ala1683=	synonymous_variant	38/39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.5049C>T	p.Ala1683=	synonymous_variant	38/39	5	NM_001271.4	ENSP00000377747	P1
CHD2	ENST00000626874.2	c.5049C>T	p.Ala1683=	synonymous_variant	38/38	1		ENSP00000486629
CHD2	ENST00000625662.3	c.*1220C>T		3_prime_UTR_variant, NMD_transcript_variant	34/35	5		ENSP00000486007
CHD2	ENST00000627460.1	c.*181C>T		3_prime_UTR_variant, NMD_transcript_variant	4/5	5		ENSP00000485982

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000629

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 251468 Hom.: 0 AF XY: 0.00134 AC XY: 182 AN XY: 135906

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00186 AC: 2724 AN: 1461886 Hom.: 2 Cov.: 35 AF XY: 0.00190 AC XY: 1379 AN XY: 727246

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152082 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74358

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHD2: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 12, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2016

This 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. -

Developmental and epileptic encephalopathy 94 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.9
DANN	Benign	0.76
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: rs139534358; hg19: chr15-93563384;