15-93014724-G-C

Position:

chr15-93014724-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 -19 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=0.0034458637).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2954 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4 linkuse as main transcript	c.4721G>C	p.Gly1574Ala	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.4721G>C	p.Gly1574Ala	missense_variant	37/39	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

GnomAD3 exomes

AF:

0.0206

AC:

5173

AN:

251390

Hom.:

AF XY:

0.0208

AC XY:

2831

AN XY:

135872

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 SAS exome

AF:

0.00382

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

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.00816

Gnomad4 ASJ exome

AF:

0.0143

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00421

Gnomad4 FIN exome

AF:

0.0390

Gnomad4 NFE exome

AF:

0.0304

Gnomad4 OTH exome

AF:

0.0211

GnomAD4 genome

AF:

0.0194

AC:

2954

AN:

152174

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1363

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00527

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.0403

Gnomad4 NFE

AF:

0.0301

Gnomad4 OTH

AF:

0.0133

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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

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

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