7-137015856-A-T

Variant names:

• chr7-137015856-A-T
• rs146328962
• NM_001006630.2:c.991A>T
• CHRM2 p.Thr331Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.15
• 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: 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	NM_001006630.2	MANE Select	c.991A>T	p.Thr331Ser	missense	Exon 4 of 4	NP_001006631.1	P08172
	CHRM2	NM_000739.3		c.991A>T	p.Thr331Ser	missense	Exon 4 of 4	NP_000730.1	P08172
	CHRM2	NM_001006626.3		c.991A>T	p.Thr331Ser	missense	Exon 5 of 5	NP_001006627.1	A4D1Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	ENST00000680005.1	MANE Select	c.991A>T	p.Thr331Ser	missense	Exon 4 of 4	ENSP00000505686.1	P08172
	CHRM2	ENST00000320658.9	TSL:1	c.991A>T	p.Thr331Ser	missense	Exon 3 of 3	ENSP00000319984.5	P08172
	CHRM2	ENST00000401861.1	TSL:1	c.991A>T	p.Thr331Ser	missense	Exon 5 of 5	ENSP00000384401.1	P08172

Frequencies

GnomAD3 genomes AF: 0.000876 AC: 133 AN: 151874 Hom.: 1 Cov.: 32

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

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.: 10 Cov.: 31 AF XY: 0.000394 AC XY: 286 AN XY: 726806

African (AFR) AF: 0.000180 AC: 6 AN: 33420

American (AMR) AF: 0.000112 AC: 5 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0118 AC: 467 AN: 39648

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111444

Other (OTH) AF: 0.00272 AC: 164 AN: 60346

GnomAD4 genome AF: 0.000855 AC: 130 AN: 151992 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74294

African (AFR) AF: 0.000193 AC: 8 AN: 41494

American (AMR) AF: 0.000393 AC: 6 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0215 AC: 110 AN: 5120

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.000880

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.82	N
REVEL	Benign	0.048
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Varity_R		0.036
gMVP		0.14
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs146328962;

hg19: chr7-136700603;

COSMIC: COSV57766687;