rs139646715

Positions:

chr15-93014765-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001271.4(CHD2):c.4762C>T(p.Arg1588Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

CHD2
NM_001271.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD2. . Gene score misZ 5.2052 (greater than the threshold 3.09). Trascript score misZ 6.0204 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy 94, complex neurodevelopmental disorder, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.049595863).

BP6

Variant 15-93014765-C-T is Benign according to our data. Variant chr15-93014765-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4 linkuse as main transcript	c.4762C>T	p.Arg1588Trp	missense_variant	37/39	ENST00000394196.9	NP_001262.3	O14647-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9 linkuse as main transcript	c.4762C>T	p.Arg1588Trp	missense_variant	37/39	5	NM_001271.4	ENSP00000377747.4		O14647-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000310

AC:

AN:

251468

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000882

AC:

1289

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

621

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.00185

GnomAD4 genome

AF:

0.000480

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000971

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy 94

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CHD2: BS1 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2017

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. -

CHD2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2021

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;D

Eigen

Benign

-0.087

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.081

MetaRNN

Benign

0.050

T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.2

.;D

REVEL

Uncertain

0.32

Sift

Benign

0.066

.;T

Sift4G

Uncertain

0.042

D;T

Polyphen

0.025

B;B

Vest4

0.41

MVP

0.84

MPC

0.26

ClinPred

0.11

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.51

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over