NM_001271.4:c.4219T>A

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.4219T>A(p.Ser1407Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,600,670 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. S1407Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 32)

Exomes 𝑓: 0.017 ( 286 hom. )

Consequence

CHD2
NM_001271.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.32

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104431400

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=0.0030409098).

BP6

Variant 15-93002258-T-A is Benign according to our data. Variant chr15-93002258-T-A is described in ClinVar as Benign. ClinVar VariationId is 238881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1784/151660) while in subpopulation SAS AF = 0.0309 (148/4782). AF 95% confidence interval is 0.0269. There are 21 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1784 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4 link	c.4219T>A	p.Ser1407Thr	missense_variant	Exon 33 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.4219T>A	p.Ser1407Thr	missense_variant	Exon 33 of 39	5	NM_001271.4	ENSP00000377747.4		O14647-1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1784

AN:

151542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00272

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00755

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0309

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0145

AC:

3459

AN:

238660

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00666

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0169

AC:

24456

AN:

1449010

Hom.:

286

Cov.:

AF XY:

0.0174

AC XY:

12575

AN XY:

720908

show subpopulations

African (AFR)

AF:

0.00265

AC:

AN:

32448

American (AMR)

AF:

0.00695

AC:

297

AN:

42756

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

288

AN:

25956

East Asian (EAS)

AF:

0.000127

AC:

AN:

39386

South Asian (SAS)

AF:

0.0308

AC:

2579

AN:

83612

European-Finnish (FIN)

AF:

0.0194

AC:

1035

AN:

53318

Middle Eastern (MID)

AF:

0.0263

AC:

151

AN:

5736

European-Non Finnish (NFE)

AF:

0.0172

AC:

18999

AN:

1105888

Other (OTH)

AF:

0.0170

AC:

1016

AN:

59910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1130

2261

3391

4522

5652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

730

1460

2190

2920

3650

<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:

0.0118

AC:

1784

AN:

151660

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

917

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.00271

AC:

112

AN:

41360

American (AMR)

AF:

0.00754

AC:

115

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3460

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.0309

AC:

148

AN:

4782

European-Finnish (FIN)

AF:

0.0173

AC:

181

AN:

10492

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0170

AC:

1152

AN:

67850

Other (OTH)

AF:

0.0143

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

178

268

357

446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0144

Hom.:

Bravo

AF:

0.00999

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0153

AC:

1854

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 13, 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. -

Inborn genetic diseases

Benign:1

Jun 07, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.060

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.066

.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.014

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.55

N;N

PhyloP100

2.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.32

.;N

REVEL

Benign

0.019

Sift

Benign

0.63

.;T

Sift4G

Benign

0.59

T;T

Polyphen

0.19

B;B

Vest4

0.083

MPC

0.23

ClinPred

0.0067

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.18

Mutation Taster

=98/2

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