15-93014724-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001271.4(CHD2):c.4721G>C(p.Gly1574Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0257 in 1,613,986 control chromosomes in the GnomAD database, including 635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1574E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 38 hom., cov: 32)

Exomes 𝑓: 0.026 ( 597 hom. )

Consequence

CHD2
NM_001271.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.86

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 94
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

CHD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034458637).

BP6

Variant 15-93014724-G-C is Benign according to our data. Variant chr15-93014724-G-C is described in ClinVar as Benign. ClinVar VariationId is 257712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0194 (2954/152174) while in subpopulation NFE AF = 0.0301 (2044/67988). AF 95% confidence interval is 0.029. There are 38 homozygotes in GnomAd4. There are 1363 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2954 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4 link	c.4721G>C	p.Gly1574Ala	missense_variant	Exon 37 of 39	ENST00000394196.9	NP_001262.3	O14647-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9 link	c.4721G>C	p.Gly1574Ala	missense_variant	Exon 37 of 39	5	NM_001271.4	ENSP00000377747.4		O14647-1

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2954

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00529

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0403

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0301

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0206

AC:

5173

AN:

251390

AF XY:

0.0208

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0403

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0263

AC:

38452

AN:

1461812

Hom.:

597

Cov.:

AF XY:

0.0257

AC XY:

18694

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00376

AC:

126

AN:

33480

American (AMR)

AF:

0.00816

AC:

365

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

374

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00421

AC:

363

AN:

86250

European-Finnish (FIN)

AF:

0.0390

AC:

2082

AN:

53418

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0304

AC:

33853

AN:

1111946

Other (OTH)

AF:

0.0211

AC:

1276

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1855

3710

5566

7421

9276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1226

2452

3678

4904

6130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0194

AC:

2954

AN:

152174

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1363

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00527

AC:

219

AN:

41520

American (AMR)

AF:

0.0103

AC:

157

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00353

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0403

AC:

427

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0301

AC:

2044

AN:

67988

Other (OTH)

AF:

0.0133

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0217

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00501

AC:

ESP6500EA

AF:

0.0286

AC:

246

ExAC

AF:

0.0225

AC:

2728

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0268

EpiControl

AF:

0.0265

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 12, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 25, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.068

.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.078

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

6.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.65

.;N

REVEL

Uncertain

0.36

Sift

Benign

0.89

.;T

Sift4G

Benign

0.87

T;T

Polyphen

0.14

B;B

Vest4

0.070

MPC

0.27

ClinPred

0.033

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.24

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over