Genetic Variant CHRM5:c.-142C>T (chr15-34018399-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000557872.1(CHRM5):c.-142C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 151,980 control chromosomes in the GnomAD database, including 2,088 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 0.15 ( 2088 hom., cov: 32)

Exomes 𝑓: 0.060 ( 0 hom. )

Consequence

CHRM5
ENST00000557872.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.145

Publications

6 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=-0.94).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM5	NM_012125.4 link	c.-407-28141C>T		intron_variant	Intron 1 of 2	ENST00000383263.7	NP_036257.1	P08912A0A024R9I2Q8IVW0
AVEN	NM_020371.3 link	c.268-15190G>A		intron_variant	Intron 1 of 5	ENST00000306730.8	NP_065104.1	Q9NQS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM5	ENST00000383263.7 link	c.-407-28141C>T		intron_variant	Intron 1 of 2	2	NM_012125.4	ENSP00000372750.5		P08912
AVEN	ENST00000306730.8 link	c.268-15190G>A		intron_variant	Intron 1 of 5	1	NM_020371.3	ENSP00000306822.3		Q9NQS1

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22575

AN:

151778

Hom.:

2090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0698

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.347

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.0917

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.163

GnomAD4 exome

AF:

0.0595

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0536

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

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)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0588

AC:

AN:

Other (OTH)

AF:

0.100

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.149

AC:

22567

AN:

151896

Hom.:

2088

Cov.:

AF XY:

0.149

AC XY:

11047

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.0697

AC:

2883

AN:

41384

American (AMR)

AF:

0.148

AC:

2264

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

1202

AN:

3468

East Asian (EAS)

AF:

0.00368

AC:

AN:

5168

South Asian (SAS)

AF:

0.0916

AC:

441

AN:

4814

European-Finnish (FIN)

AF:

0.232

AC:

2443

AN:

10550

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12725

AN:

67956

Other (OTH)

AF:

0.162

AC:

341

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

971

1942

2912

3883

4854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.0794

Hom.:

101

Bravo

AF:

0.141

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

3.8

(source)

DANN

Benign

0.72

PhyloP100

0.14

PromoterAI

-0.014

Neutral

(source)

Mutation Taster

=299/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over