rs61756301

chr15-93002258-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/19 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. S1407I) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD2
• 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 id is 238881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-93002258-T-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1784 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.4219T>A	p.Ser1407Thr	missense_variant	33/39	ENST00000394196.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.4219T>A	p.Ser1407Thr	missense_variant	33/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1784 AN: 151542 Hom.: 21 Cov.: 32

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

GnomAD3 exomes AF: 0.0145 AC: 3459 AN: 238660 Hom.: 67 AF XY: 0.0162 AC XY: 2095 AN XY: 129264

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 SAS exome AF: 0.0312

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.: 28 AF XY: 0.0174 AC XY: 12575 AN XY: 720908

Gnomad4 AFR exome AF: 0.00265

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0308

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0118 AC: 1784 AN: 151660 Hom.: 21 Cov.: 32 AF XY: 0.0124 AC XY: 917 AN XY: 74120

Gnomad4 AFR AF: 0.00271

Gnomad4 AMR AF: 0.00754

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0309

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.0144 Hom.: 23

Bravo AF: 0.00999

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0171 AC: 147

ExAC AF: 0.0153 AC: 1854

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.89
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.59	T;T
Polyphen		0.19	B;B
Vest4		0.083
MPC		0.23
ClinPred		0.0067	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.18

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61756301; hg19: chr15-93545488; COSMIC: COSV104431400; COSMIC: COSV104431400;