Genetic Variant CHRM5:c.*2673T>C (chr15-34066989-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012125.4(CHRM5):c.*2673T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 151,996 control chromosomes in the GnomAD database, including 20,535 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 0.47 ( 20527 hom., cov: 31)

Exomes 𝑓: 0.68 ( 8 hom. )

Consequence

CHRM5
NM_012125.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.836

Publications

11 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CHRM5	NM_012125.4 link	c.*2673T>C	3_prime_UTR_variant	Exon 3 of 3	ENST00000383263.7	NP_036257.1	P08912A0A024R9I2Q8IVW0
CHRM5	NM_001320917.2 link	c.*2673T>C	3_prime_UTR_variant	Exon 2 of 2		NP_001307846.1	P08912A0A024R9I2
AVEN	XM_011521818.3 link	c.72+3599A>G	intron_variant	Intron 2 of 6		XP_011520120.1
AVEN	XM_047432882.1 link	c.72+3599A>G	intron_variant	Intron 3 of 7		XP_047288838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM5	ENST00000383263.7 link	c.*2673T>C		3_prime_UTR_variant	Exon 3 of 3	2	NM_012125.4	ENSP00000372750.5		P08912
AVEN	ENST00000675287.1 link	n.785-178A>G		intron_variant	Intron 2 of 11

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71860

AN:

151850

Hom.:

20520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.548

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.511

Gnomad FIN

AF:

0.556

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.642

Gnomad OTH

AF:

0.512

GnomAD4 exome

AF:

0.679

AC:

AN:

Hom.:

Cov.:

AF XY:

0.792

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.473

AC:

71873

AN:

151968

Hom.:

20527

Cov.:

AF XY:

0.471

AC XY:

34953

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.141

AC:

5843

AN:

41470

American (AMR)

AF:

0.548

AC:

8368

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1576

AN:

3462

East Asian (EAS)

AF:

0.461

AC:

2378

AN:

5156

South Asian (SAS)

AF:

0.512

AC:

2460

AN:

4804

European-Finnish (FIN)

AF:

0.556

AC:

5865

AN:

10540

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.642

AC:

43650

AN:

67950

Other (OTH)

AF:

0.513

AC:

1082

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1579

3158

4736

6315

7894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.579

Hom.:

17199

Bravo

AF:

0.455

Asia WGS

AF:

0.509

AC:

1768

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.5

(source)

DANN

Benign

0.75

PhyloP100

-0.84

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over