11-46385307-G-A

Variant names:

• chr11-46385307-G-A
• rs2229163
• NM_000741.5:c.1251C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000682254.1(CHRM4):​c.1251C>T​(p.Asn417Asn) 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 ENST00000682254.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682254.1. 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
	CHRM4	NM_000741.5	MANE Select	c.1251C>T	p.Asn417Asn	synonymous	Exon 2 of 2	NP_000732.2
	CHRM4	NM_001366692.2		c.1251C>T	p.Asn417Asn	synonymous	Exon 2 of 2	NP_001353621.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM4	ENST00000682254.1	MANE Select	c.1251C>T	p.Asn417Asn	synonymous	Exon 2 of 2	ENSP00000507561.1
	CHRM4	ENST00000433765.3	TSL:6	c.1251C>T	p.Asn417Asn	synonymous	Exon 1 of 1	ENSP00000409378.2

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

GnomAD2 exomes AF: 0.0101 AC: 2532 AN: 250260 AF XY: 0.00735

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 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

African (AFR) AF: 0.132 AC: 4412 AN: 33480

American (AMR) AF: 0.00857 AC: 383 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000163 AC: 181 AN: 1111890

Other (OTH) AF: 0.00893 AC: 539 AN: 60388

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

African (AFR) AF: 0.128 AC: 5329 AN: 41574

American (AMR) AF: 0.0157 AC: 240 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0198 Hom.: 131

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.86
PhyloP100		-0.56
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: rs2229163; hg19: chr11-46406857;