rs138886480

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_001006630.2(CHRM2):c.703C>A(p.Leu235Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CHRM2
NM_001006630.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.70

Variant links:

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]

CHRM2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0077776313).

BP6

Variant 7-137015568-C-A is Benign according to our data. Variant chr7-137015568-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 422877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM2	NM_001006630.2 linkuse as main transcript	c.703C>A	p.Leu235Met	missense_variant	4/4	ENST00000680005.1
LOC349160	NR_046103.1 linkuse as main transcript	n.341+17226G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM2	ENST00000680005.1 linkuse as main transcript	c.703C>A	p.Leu235Met	missense_variant	4/4		NM_001006630.2	P1
	ENST00000586239.5 linkuse as main transcript	n.273+17226G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00409

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000301

AC:

AN:

249576

Hom.:

AF XY:

0.000311

AC XY:

AN XY:

134916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00403

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1460890

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00535

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000138

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00410

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000302

ExAC

AF:

0.000297

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2017

p.Leu235Met in exon 5 of CHRM2: This variant is not expected to have clinical si gnificance because it has been identified in 0.43% (35/8206) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs138886480). -

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.067

T;T;T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.77

.;.;.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.4

M;M;M;M

MutationTaster

Benign

0.75

N;N;N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.090

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.76

P;P;P;P

Vest4

0.24

MVP

0.86

MPC

1.2

ClinPred

0.11

GERP RS

3.6

Varity_R

0.13

gMVP

0.20

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

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