rs2067481

Variant names:

• chr1-239907644-G-A
• rs2067481
• NM_001375978.1:c.193G>A
• CHRM3 p.Val65Ile

Variant summary

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

The NM_001375978.1(CHRM3):​c.193G>A​(p.Val65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,614,116 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.016 (259 hom.)
• Consequence: CHRM3 NM_001375978.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0850
• Publications: 13 publications found

Genes affected

CHRM3 (HGNC:1952): (cholinergic receptor muscarinic 3) 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 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 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

CHRM3-AS1 (HGNC:40150): (CHRM3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00343284).
• BP6: Variant 1-239907644-G-A is Benign according to our data. Variant chr1-239907644-G-A is described in ClinVar as Benign. ClinVar VariationId is 1576872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0135 (2055/152230) while in subpopulation SAS AF = 0.0375 (181/4824). AF 95% confidence interval is 0.0331. There are 28 homozygotes in GnomAd4. There are 1103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375978.1. 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
	CHRM3	NM_001375978.1	MANE Select	c.193G>A	p.Val65Ile	missense	Exon 7 of 7	NP_001362907.1	P20309
	CHRM3	NM_000740.4		c.193G>A	p.Val65Ile	missense	Exon 5 of 5	NP_000731.1	P20309
	CHRM3	NM_001347716.2		c.193G>A	p.Val65Ile	missense	Exon 8 of 8	NP_001334645.1	P20309

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM3	ENST00000676153.1	MANE Select	c.193G>A	p.Val65Ile	missense	Exon 7 of 7	ENSP00000502667.1	P20309
	CHRM3	ENST00000255380.8	TSL:1	c.193G>A	p.Val65Ile	missense	Exon 5 of 5	ENSP00000255380.4	P20309
	CHRM3	ENST00000615928.5	TSL:5	c.193G>A	p.Val65Ile	missense	Exon 6 of 6	ENSP00000482377.1	P20309

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2054 AN: 152112 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0174 AC: 4386 AN: 251400 AF XY: 0.0197

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00348

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0158 AC: 23099 AN: 1461886 Hom.: 259 Cov.: 31 AF XY: 0.0168 AC XY: 12200 AN XY: 727242

African (AFR) AF: 0.00230 AC: 77 AN: 33480

American (AMR) AF: 0.00458 AC: 205 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00872 AC: 228 AN: 26136

East Asian (EAS) AF: 0.00202 AC: 80 AN: 39698

South Asian (SAS) AF: 0.0431 AC: 3716 AN: 86258

European-Finnish (FIN) AF: 0.0421 AC: 2247 AN: 53420

Middle Eastern (MID) AF: 0.0227 AC: 131 AN: 5768

European-Non Finnish (NFE) AF: 0.0140 AC: 15541 AN: 1112006

Other (OTH) AF: 0.0145 AC: 874 AN: 60396

GnomAD4 genome AF: 0.0135 AC: 2055 AN: 152230 Hom.: 28 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74440

African (AFR) AF: 0.00274 AC: 114 AN: 41544

American (AMR) AF: 0.00576 AC: 88 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00837 AC: 29 AN: 3466

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5170

South Asian (SAS) AF: 0.0375 AC: 181 AN: 4824

European-Finnish (FIN) AF: 0.0455 AC: 482 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1100 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0132 Hom.: 67

Bravo AF: 0.00861

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0151

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.28
DANN	Benign	0.77
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.085
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.086
Sift	Benign	0.49	T
Sift4G	Benign	0.084	T
Varity_R		0.025
gMVP		0.38
Mutation Taster		=98/2	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

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

Other links and lift over

dbSNP: rs2067481;

hg19: chr1-240070944;

COSMIC: COSV55091298;