rs2229163

Positions:

• chr11-46385307-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000741.5(CHRM4):​c.1251C>T​(p.Asn417=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,613,950 control chromosomes in the GnomAD database, including 697 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 0.037 (367 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (330 hom.)
• Consequence: CHRM4 NM_000741.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560

Genes affected

CHRM4 (HGNC:1953): (cholinergic receptor muscarinic 4) 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 clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-0.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM4	NM_000741.5	c.1251C>T	p.Asn417=	synonymous_variant	2/2	ENST00000682254.1	NP_000732.2
CHRM4	NM_001366692.2	c.1251C>T	p.Asn417=	synonymous_variant	2/2		NP_001353621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM4	ENST00000682254.1	c.1251C>T	p.Asn417=	synonymous_variant	2/2		NM_000741.5	ENSP00000507561	P1
CHRM4	ENST00000433765.3	c.1251C>T	p.Asn417=	synonymous_variant	1/1			ENSP00000409378	P1

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5662 AN: 152210 Hom.: 367 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0101 AC: 2532 AN: 250260 Hom.: 149 AF XY: 0.00735 AC XY: 996 AN XY: 135578

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00784

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00384 AC: 5613 AN: 1461622 Hom.: 330 Cov.: 32 AF XY: 0.00331 AC XY: 2408 AN XY: 727072

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.00857

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.00893

GnomAD4 genome AF: 0.0372 AC: 5670 AN: 152328 Hom.: 367 Cov.: 33 AF XY: 0.0358 AC XY: 2664 AN XY: 74494

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0178 Hom.: 95

Bravo AF: 0.0440

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229163; hg19: chr11-46406857;