rs76394680

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.87

Publications

11 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 -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 Benign/Likely_benign. ClinVar VariationId is 227248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRM2	NM_001006630.2	MANE Select	c.691G>A	p.Val231Ile	missense	Exon 4 of 4	NP_001006631.1	P08172
CHRM2	NM_000739.3		c.691G>A	p.Val231Ile	missense	Exon 4 of 4	NP_000730.1	P08172
CHRM2	NM_001006626.3		c.691G>A	p.Val231Ile	missense	Exon 5 of 5	NP_001006627.1	A4D1Q0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRM2	ENST00000680005.1	MANE Select	c.691G>A	p.Val231Ile	missense	Exon 4 of 4	ENSP00000505686.1	P08172
CHRM2	ENST00000320658.9	TSL:1	c.691G>A	p.Val231Ile	missense	Exon 3 of 3	ENSP00000319984.5	P08172
CHRM2	ENST00000401861.1	TSL:1	c.691G>A	p.Val231Ile	missense	Exon 5 of 5	ENSP00000384401.1	P08172

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

525

AN:

151844

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00537

AC XY:

3905

AN XY:

726742

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

33440

American (AMR)

AF:

0.00121

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00475

AC:

124

AN:

26116

East Asian (EAS)

AF:

0.000608

AC:

AN:

39474

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00445

AC:

237

AN:

53318

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00670

AC:

7444

AN:

1111564

Other (OTH)

AF:

0.00615

AC:

371

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

565

1130

1696

2261

2826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00345

AC:

525

AN:

151960

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

230

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41484

American (AMR)

AF:

0.00177

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3466

East Asian (EAS)

AF:

0.000586

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00425

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00556

AC:

378

AN:

67928

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

143

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:

0.00464

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00296

AC:

359

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Dilated Cardiomyopathy, Dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.053

Eigen

Benign

-0.10

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.67

PhyloP100

2.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.18

REVEL

Benign

0.047

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.061

MVP

0.87

MPC

0.45

ClinPred

0.0079

GERP RS

5.4

Varity_R

0.16

gMVP

0.23

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over