rs138193709

Variant names:

• chr7-137015725-C-G
• rs138193709
• NM_001006630.2:c.860C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-137015725-C-G
• chr7-137015725-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001006630.2(CHRM2):​c.860C>G​(p.Thr287Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,613,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: CHRM2 NM_001006630.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.08
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100696385).
• BP6: Variant 7-137015725-C-G is Benign according to our data. Variant chr7-137015725-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228517.

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.860C>G	p.Thr287Ser	missense	Exon 4 of 4	NP_001006631.1
	CHRM2	NM_000739.3		c.860C>G	p.Thr287Ser	missense	Exon 4 of 4	NP_000730.1
	CHRM2	NM_001006626.3		c.860C>G	p.Thr287Ser	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.860C>G	p.Thr287Ser	missense	Exon 4 of 4	ENSP00000505686.1
	CHRM2	ENST00000320658.9	TSL:1	c.860C>G	p.Thr287Ser	missense	Exon 3 of 3	ENSP00000319984.5
	CHRM2	ENST00000401861.1	TSL:1	c.860C>G	p.Thr287Ser	missense	Exon 5 of 5	ENSP00000384401.1

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 75 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 249974 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461248 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 726934

African (AFR) AF: 0.00239 AC: 80 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111638

Other (OTH) AF: 0.0000994 AC: 6 AN: 60356

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74322

African (AFR) AF: 0.00176 AC: 73 AN: 41520

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67928

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000586

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.89	L
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.074
Sift	Benign	0.58	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.34		Loss of sheet (P = 7e-04)
MVP		0.83
MPC		0.50
ClinPred		0.035	T
GERP RS		5.4
Varity_R		0.10
gMVP		0.33
Mutation Taster		=62/38	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

Other links and lift over

dbSNP: rs138193709; hg19: chr7-136700472;