rs142006633

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001006630.2(CHRM2):c.773A>G(p.Asn258Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,034 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

CHRM2
NM_001006630.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.68

Publications

3 publications found

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:

ENSG00000234352 (HGNC:):

ENSG00000234352 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=0.0057683587).

BP6

Variant 7-137015638-A-G is Benign according to our data. Variant chr7-137015638-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00124 (1807/1461054) while in subpopulation MID AF = 0.0191 (110/5762). AF 95% confidence interval is 0.0162. There are 4 homozygotes in GnomAdExome4. There are 939 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM2	NM_001006630.2 link	c.773A>G	p.Asn258Ser	missense_variant	Exon 4 of 4	ENST00000680005.1	NP_001006631.1	P08172A4D1Q0Q6SL56Q86SJ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM2	ENST00000680005.1 link	c.773A>G	p.Asn258Ser	missense_variant	Exon 4 of 4		NM_001006630.2	ENSP00000505686.1		P08172

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00401

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00145

AC:

362

AN:

249420

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00508

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00124

AC:

1807

AN:

1461054

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

939

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33430

American (AMR)

AF:

0.00238

AC:

106

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

117

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.000603

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.0191

AC:

110

AN:

5762

European-Non Finnish (NFE)

AF:

0.00113

AC:

1256

AN:

1111620

Other (OTH)

AF:

0.00232

AC:

140

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00138

AC:

209

AN:

151980

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41492

American (AMR)

AF:

0.00400

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00149

AC:

101

AN:

67896

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00213

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00338

EpiControl

AF:

0.00297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 13, 2018

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. -

Jun 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn258Ser in exon 5 of CHRM2: This variant is not expected to have clinical si gnificance because of its population frequency and lack of evolutionary conserva tion. It is present in 0.2% (135/66208) of European chromosomes screened by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1420 06633). Two mammals and >10 bird, reptile and fish species carrying a serine (Se r) at position 258, supporting that this change may be tolerated. -

Dilated Cardiomyopathy, Dominant

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHRM2-related disorder

Benign:1

Apr 07, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

0.058

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.043

T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.80

.;.;.;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

N;N;N;N

PhyloP100

1.7

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.090

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.96

T;T;T;T

Sift4G

Benign

0.87

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.016

MVP

0.68

MPC

0.44

ClinPred

0.0067

GERP RS

4.3

Varity_R

0.039

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

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

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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