rs146328962

chr7-137015856-A-Cchr7-137015856-A-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.991A>C(p.Thr331Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T331S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRM2 NM_001006630.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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=0.14114153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM2	NM_001006630.2	c.991A>C	p.Thr331Pro	missense_variant	4/4	ENST00000680005.1
LOC349160	NR_046103.1	n.341+16938T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM2	ENST00000680005.1	c.991A>C	p.Thr331Pro	missense_variant	4/4		NM_001006630.2	P1
	ENST00000586239.5	n.273+16938T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 331 of the CHRM2 protein (p.Thr331Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.033	T;T;T;T
Eigen	Benign	-0.0094
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	0.70	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.56	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.30	B;B;B;B
Vest4		0.069
MutPred		0.37		Gain of catalytic residue at T331 (P = 0.0102);Gain of catalytic residue at T331 (P = 0.0102);Gain of catalytic residue at T331 (P = 0.0102);Gain of catalytic residue at T331 (P = 0.0102);
MVP		0.84
MPC		0.72
ClinPred		0.57	D
GERP RS		4.2
Varity_R		0.11
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-136700603;