rs117844037

Positions:

chr15-92939634-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001271.4(CHD2):c.608A>G(p.Lys203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,170 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 14 hom. )

Consequence

CHD2
NM_001271.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.831

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 -15 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=0.005824387).

BP6

Variant 15-92939634-A-G is Benign according to our data. Variant chr15-92939634-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-92939634-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4 linkuse as main transcript	c.608A>G	p.Lys203Arg	missense_variant	7/39	ENST00000394196.9	NP_001262.3
CHD2	NM_001042572.3 linkuse as main transcript	c.608A>G	p.Lys203Arg	missense_variant	7/13		NP_001036037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9 linkuse as main transcript	c.608A>G	p.Lys203Arg	missense_variant	7/39	5	NM_001271.4	ENSP00000377747	P1	O14647-1

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

369

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00328

AC:

825

AN:

251418

Hom.:

AF XY:

0.00297

AC XY:

404

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00627

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00371

AC:

5422

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2576

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00245

Gnomad4 NFE exome

AF:

0.00451

Gnomad4 OTH exome

AF:

0.00349

GnomAD4 genome

AF:

0.00242

AC:

369

AN:

152300

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00451

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00362

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00436

AC:

530

EpiCase

AF:

0.00409

EpiControl

AF:

0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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	May 01, 2024	CHD2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2018	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	Genetic Services Laboratory, University of Chicago	Dec 18, 2017	- -

Developmental and epileptic encephalopathy 94

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2018

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.058

.;T;T;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

T;T;T;T;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.0058

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.31

N;N;.;N;.

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.020

.;N;.;N;.

REVEL

Benign

0.075

Sift

Benign

0.44

.;T;.;T;.

Sift4G

Benign

0.61

T;T;T;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.13

MVP

0.64

MPC

0.39

ClinPred

0.0073

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.032

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