rs6963819

Variant names:

• chr7-136903362-G-A
• rs6963819
• NM_001006630.2:c.-125+33944G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001006630.2(CHRM2):​c.-125+33944G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 389,704 control chromosomes in the GnomAD database, including 78,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (34206 hom., cov: 31)
  • Exomes 𝑓: 0.61 (44694 hom.)
• Consequence: CHRM2 NM_001006630.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.367
• Publications: 9 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:):

MIR490 (HGNC:32075): (microRNA 490) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	NM_001006630.2	MANE Select	c.-125+33944G>A		intron	N/A	NP_001006631.1
	CHRM2	NM_000739.3		c.-125+33944G>A		intron	N/A	NP_000730.1
	CHRM2	NM_001006626.3		c.-203+33944G>A		intron	N/A	NP_001006627.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	ENST00000680005.1	MANE Select	c.-125+33944G>A		intron	N/A	ENSP00000505686.1
	CHRM2	ENST00000320658.9	TSL:1	c.-47+33944G>A		intron	N/A	ENSP00000319984.5
	CHRM2	ENST00000401861.1	TSL:1	c.-203+33944G>A		intron	N/A	ENSP00000384401.1

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100724 AN: 151742 Hom.: 34151 Cov.: 31

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.647

GnomAD4 exome AF: 0.607 AC: 144340 AN: 237844 Hom.: 44694 Cov.: 0 AF XY: 0.605 AC XY: 81623 AN XY: 134996

African (AFR) AF: 0.772 AC: 3148 AN: 4076

American (AMR) AF: 0.392 AC: 5483 AN: 13994

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 4360 AN: 6694

East Asian (EAS) AF: 0.442 AC: 3207 AN: 7248

South Asian (SAS) AF: 0.564 AC: 23635 AN: 41894

European-Finnish (FIN) AF: 0.646 AC: 17562 AN: 27166

Middle Eastern (MID) AF: 0.621 AC: 1197 AN: 1928

European-Non Finnish (NFE) AF: 0.636 AC: 79183 AN: 124444

Other (OTH) AF: 0.631 AC: 6565 AN: 10400

GnomAD4 genome AF: 0.664 AC: 100828 AN: 151860 Hom.: 34206 Cov.: 31 AF XY: 0.660 AC XY: 48988 AN XY: 74222

African (AFR) AF: 0.788 AC: 32675 AN: 41464

American (AMR) AF: 0.523 AC: 7962 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2223 AN: 3468

East Asian (EAS) AF: 0.455 AC: 2328 AN: 5122

South Asian (SAS) AF: 0.561 AC: 2703 AN: 4818

European-Finnish (FIN) AF: 0.661 AC: 6994 AN: 10576

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43842 AN: 67880

Other (OTH) AF: 0.650 AC: 1368 AN: 2104

Alfa AF: 0.644 Hom.: 113779

Bravo AF: 0.656

Asia WGS AF: 0.551 AC: 1916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.37
DANN	Benign	0.18
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs6963819; hg19: chr7-136588109; COSMIC: COSV57766314; COSMIC: COSV57766314;