rs117844037

chr15-92939634-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K203E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.831

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD2
• 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 GnomAd at 369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.608A>G	p.Lys203Arg	missense_variant	7/39	ENST00000394196.9
CHD2	NM_001042572.3	c.608A>G	p.Lys203Arg	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.608A>G	p.Lys203Arg	missense_variant	7/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152182 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00297 AC XY: 404 AN XY: 135874

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.: 14 Cov.: 30 AF XY: 0.00354 AC XY: 2576 AN XY: 727234

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.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74480

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.: 4

Bravo AF: 0.00226

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00436 AC: 530

EpiCase AF: 0.00409

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CHD2: BP4, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 18, 2017	- -
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. -

Developmental and epileptic encephalopathy 94 Benign:2

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

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;T;T;T;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.31	N;N;.;N;.
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Uncertain	0.49	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	T
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

Other links and lift over

dbSNP: rs117844037; hg19: chr15-93482864; COSMIC: COSV99046909; COSMIC: COSV99046909;