Genetic Variant CHRM5:c.-408+15926G>A (chr15-33985076-G-A) – 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.-408+15926G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 151,934 control chromosomes in the GnomAD database, including 20,705 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 ( 20705 hom., cov: 31)

Consequence

CHRM5
NM_012125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.468

Publications

4 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=-0.8).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CHRM5	NM_012125.4	MANE Select	c.-408+15926G>A	intron	N/A	NP_036257.1
AVEN	NM_020371.3	MANE Select	c.445+17956C>T	intron	N/A	NP_065104.1
CHRM5	NM_001320917.2		c.-76+15926G>A	intron	N/A	NP_001307846.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-408+15926G>A	intron	N/A	ENSP00000372750.5
AVEN	ENST00000306730.8	TSL:1 MANE Select	c.445+17956C>T	intron	N/A	ENSP00000306822.3
CHRM5	ENST00000560035.1	TSL:4	c.-76+15926G>A	intron	N/A	ENSP00000452742.1

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

72146

AN:

151816

Hom.:

20697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.559

Gnomad AMR

AF:

0.569

Gnomad ASJ

AF:

0.470

Gnomad EAS

AF:

0.523

Gnomad SAS

AF:

0.524

Gnomad FIN

AF:

0.540

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.639

Gnomad OTH

AF:

0.531

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.475

AC:

72156

AN:

151934

Hom.:

20705

Cov.:

AF XY:

0.473

AC XY:

35139

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.139

AC:

5772

AN:

41462

American (AMR)

AF:

0.569

AC:

8687

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

1623

AN:

3456

East Asian (EAS)

AF:

0.523

AC:

2691

AN:

5142

South Asian (SAS)

AF:

0.524

AC:

2490

AN:

4750

European-Finnish (FIN)

AF:

0.540

AC:

5711

AN:

10582

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.639

AC:

43424

AN:

67954

Other (OTH)

AF:

0.532

AC:

1122

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1591

3182

4774

6365

7956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.400

Hom.:

1412

Bravo

AF:

0.460

Asia WGS

AF:

0.511

AC:

1774

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.9

(source)

DANN

Benign

0.43

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over