rs76394680

Variant names:

• chr7-137015556-G-A
• rs76394680
• NM_001006630.2:c.691G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001006630.2(CHRM2):​c.691G>A​(p.Val231Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,612,814 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. V231A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (27 hom.)
• Consequence: CHRM2 NM_001006630.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.87
• Publications: 11 publications found

Genes affected

CHRM2 (HGNC:1951): (cholinergic receptor muscarinic 2) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine to these receptors and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 2 is involved in mediation of bradycardia and a decrease in cardiac contractility. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ENSG00000234352 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066742003).
• BP6: Variant 7-137015556-G-A is Benign according to our data. Variant chr7-137015556-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM2	NM_001006630.2	c.691G>A	p.Val231Ile	missense_variant	Exon 4 of 4	ENST00000680005.1	NP_001006631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM2	ENST00000680005.1	c.691G>A	p.Val231Ile	missense_variant	Exon 4 of 4		NM_001006630.2	ENSP00000505686.1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 525 AN: 151844 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00343 AC: 856 AN: 249462 AF XY: 0.00332

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.000552

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00568 AC: 8294 AN: 1460854 Hom.: 27 Cov.: 31 AF XY: 0.00537 AC XY: 3905 AN XY: 726742

African (AFR) AF: 0.000987 AC: 33 AN: 33440

American (AMR) AF: 0.00121 AC: 54 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26116

East Asian (EAS) AF: 0.000608 AC: 24 AN: 39474

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86242

European-Finnish (FIN) AF: 0.00445 AC: 237 AN: 53318

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00670 AC: 7444 AN: 1111564

Other (OTH) AF: 0.00615 AC: 371 AN: 60326

GnomAD4 genome AF: 0.00345 AC: 525 AN: 151960 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 230 AN XY: 74264

African (AFR) AF: 0.00121 AC: 50 AN: 41484

American (AMR) AF: 0.00177 AC: 27 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00425 AC: 45 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 67928

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00464 Hom.: 5

Bravo AF: 0.00290

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00296 AC: 359

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val231Ile in exon 5 of CHRM2: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (299/65916) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs76394680). -

Oct 26, 2017

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. -

Dilated Cardiomyopathy, Dominant Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.053	T;T;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	.;.;.;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.67	N;N;N;N
PhyloP100		2.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.061
MVP		0.87
MPC		0.45
ClinPred		0.0079	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs76394680; hg19: chr7-136700303; COSMIC: COSV57764274;