7-137015856-A-T

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.991A>T(p.Thr331Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,612,986 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T331P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 10 hom. )

Consequence

CHRM2
NM_001006630.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.15

Publications

1 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=0.0027596354).

BP6

Variant 7-137015856-A-T is Benign according to our data. Variant chr7-137015856-A-T is described in ClinVar as Benign. ClinVar VariationId is 478116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000855 (130/151992) while in subpopulation EAS AF = 0.0215 (110/5120). AF 95% confidence interval is 0.0182. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM2	NM_001006630.2 link	c.991A>T	p.Thr331Ser	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 link	c.991A>T	p.Thr331Ser	missense_variant	Exon 4 of 4		NM_001006630.2	ENSP00000505686.1

Frequencies

GnomAD3 genomes

AF:

0.000876

AC:

133

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0220

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00175

AC:

438

AN:

250230

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0232

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000454

AC:

664

AN:

1460994

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

286

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33420

American (AMR)

AF:

0.000112

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.0118

AC:

467

AN:

39648

South Asian (SAS)

AF:

0.000104

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111444

Other (OTH)

AF:

0.00272

AC:

164

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000855

AC:

130

AN:

151992

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41494

American (AMR)

AF:

0.000393

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0215

AC:

110

AN:

5120

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67902

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000619

Hom.:

Bravo

AF:

0.000880

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 10, 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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr331Ser in exon 5 of CHRM2: This variant is not expected to have clinical sign ificance because it has been identified in 3.5% (7/200) of Han Chinese chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs146328962). -

Dilated Cardiomyopathy, Dominant

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.032

T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.69

.;.;.;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

N;N;N;N

PhyloP100

3.1

PrimateAI

Benign

0.43

PROVEAN

Benign

0.82

N;N;N;N

REVEL

Benign

0.048

Sift

Benign

0.81

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.040

MutPred

0.26

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.74

MPC

0.49

ClinPred

0.012

GERP RS

4.2

Varity_R

0.036

gMVP

0.14

Mutation Taster

=97/3

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