rs1554437349

Positions:

• chr7-137015659-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001006630.2(CHRM2):​c.794C>T​(p.Ala265Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CHRM2 NM_001006630.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.16

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12485647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM2	NM_001006630.2	c.794C>T	p.Ala265Val	missense_variant	4/4	ENST00000680005.1	NP_001006631.1
LOC349160	NR_046103.1	n.341+17135G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM2	ENST00000680005.1	c.794C>T	p.Ala265Val	missense_variant	4/4		NM_001006630.2	ENSP00000505686	P1
	ENST00000586239.5	n.273+17135G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461046 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2016

The p.Ala265Val variant in CHRM2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis suggest that the p.Ala265Val variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the clinical significance of the p.Ala265Val variant is uncertain. -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 504934). This variant has not been reported in the literature in individuals affected with CHRM2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 265 of the CHRM2 protein (p.Ala265Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.091	T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;.;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.49	N;N;N;N
MutationTaster	Benign	0.84	D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.057
MutPred		0.41		Gain of methylation at K264 (P = 0.0336);Gain of methylation at K264 (P = 0.0336);Gain of methylation at K264 (P = 0.0336);Gain of methylation at K264 (P = 0.0336);
MVP		0.89
MPC		0.55
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.11
gMVP		0.28

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

Other links and lift over

dbSNP: rs1554437349; hg19: chr7-136700406;