Genetic Variant CHRM5:p.Leu362Phe (chr15-34063801-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012125.4(CHRM5):c.1084C>T(p.Leu362Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CHRM5
NM_012125.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

1 publications found

Variant links:

Genes affected

CHRM5 (HGNC:1954): (cholinergic receptor muscarinic 5) 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, stimulation of this receptor is known to increase cyclic AMP levels. [provided by RefSeq, Jul 2008]

CHRM5 links:

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

AVEN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06796947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM5	NM_012125.4 link	c.1084C>T	p.Leu362Phe	missense_variant	Exon 3 of 3	ENST00000383263.7	NP_036257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHRM5	ENST00000383263.7 link	c.1084C>T	p.Leu362Phe	missense_variant	Exon 3 of 3	2	NM_012125.4	ENSP00000372750.5
CHRM5	ENST00000557872.1 link	c.1084C>T	p.Leu362Phe	missense_variant	Exon 2 of 2	1		ENSP00000453745.1
AVEN	ENST00000675287.1 link	n.1127-369G>A		intron_variant	Intron 4 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251474

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.7

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.021

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.50

.;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;N

PhyloP100

1.9

PrimateAI

Benign

0.39

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.11

Sift

Benign

0.96

T;T

Sift4G

Benign

0.90

T;T

Polyphen

0.0

B;B

Vest4

0.068

MutPred

0.33

Loss of disorder (P = 0.2092);Loss of disorder (P = 0.2092);

MVP

0.69

MPC

0.26

ClinPred

0.026

GERP RS

4.5

Varity_R

0.051

gMVP

0.16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over