rs200255240

Variant names:

• chr11-46385467-G-A
• rs200255240
• NM_000741.5:c.1091C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-46385467-G-A
• chr11-46385467-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000741.5(CHRM4):​c.1091C>T​(p.Pro364Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000875 in 1,600,876 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P364Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CHRM4 NM_000741.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14830774).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000741.5. 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
	CHRM4	NM_000741.5	MANE Select	c.1091C>T	p.Pro364Leu	missense	Exon 2 of 2	NP_000732.2
	CHRM4	NM_001366692.2		c.1091C>T	p.Pro364Leu	missense	Exon 2 of 2	NP_001353621.1	P08173

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM4	ENST00000682254.1	MANE Select	c.1091C>T	p.Pro364Leu	missense	Exon 2 of 2	ENSP00000507561.1	P08173
	CHRM4	ENST00000433765.3	TSL:6	c.1091C>T	p.Pro364Leu	missense	Exon 1 of 1	ENSP00000409378.2	P08173
	CHRM4	ENST00000855139.1		c.1091C>T	p.Pro364Leu	missense	Exon 2 of 2	ENSP00000525198.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247720 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1448508 Hom.: 0 Cov.: 32 AF XY: 0.00000976 AC XY: 7 AN XY: 717532

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.0000225 AC: 1 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 85864

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000726 AC: 8 AN: 1101334

Other (OTH) AF: 0.00 AC: 0 AN: 59704

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74520

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000413 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N
PhyloP100		4.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.20	T
Polyphen		0.44	B
Vest4		0.063
MutPred		0.56		Loss of disorder (P = 0.0245)
MVP		0.20
MPC		0.94
ClinPred		0.088	T
GERP RS		4.4
Varity_R		0.069
gMVP		0.52
Mutation Taster		=91/9	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: rs200255240; hg19: chr11-46407017; COSMIC: COSV106103510; COSMIC: COSV106103510;