chr7-137015082-G-A

Variant names:

• chr7-137015082-G-A
• rs11773032
• NM_001006630.2:c.217G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000739.3(CHRM2):​c.217G>A​(p.Gly73Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G73G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRM2 NM_000739.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90
• Publications: 1 publications found

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]

ENSG00000234352 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000739.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	NM_001006630.2	MANE Select	c.217G>A	p.Gly73Ser	missense	Exon 4 of 4	NP_001006631.1
	CHRM2	NM_000739.3		c.217G>A	p.Gly73Ser	missense	Exon 4 of 4	NP_000730.1
	CHRM2	NM_001006626.3		c.217G>A	p.Gly73Ser	missense	Exon 5 of 5	NP_001006627.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	ENST00000680005.1	MANE Select	c.217G>A	p.Gly73Ser	missense	Exon 4 of 4	ENSP00000505686.1
	CHRM2	ENST00000320658.9	TSL:1	c.217G>A	p.Gly73Ser	missense	Exon 3 of 3	ENSP00000319984.5
	CHRM2	ENST00000401861.1	TSL:1	c.217G>A	p.Gly73Ser	missense	Exon 5 of 5	ENSP00000384401.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.69		Loss of stability (P = 0.1733)
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.91
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs11773032; hg19: chr7-136699829;