Genetic Variant CHRM2:c.-508_-501delCACACACA (chr7-136868746-GCACACACA-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001006630.2(CHRM2):c.-508_-501delCACACACA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 149,568 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0051 ( 0 hom. )

Consequence

CHRM2
NM_001006630.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.33

Publications

3 publications found

Variant links:

Genes affected

CHRM2 (HGNC:1951): (cholinergic receptor muscarinic 2) 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 to these receptors 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 muscarinic cholinergic receptor 2 is involved in mediation of bradycardia and a decrease in cardiac contractility. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

CHRM2 links:

ENSG00000234352 (HGNC:):

ENSG00000234352 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRM2	NM_001006630.2	MANE Select	c.-508_-501delCACACACA	5_prime_UTR	Exon 1 of 4	NP_001006631.1	P08172
CHRM2	NM_001006627.3		c.-430_-423delCACACACA	5_prime_UTR	Exon 1 of 3	NP_001006628.1	A4D1Q0
CHRM2	NM_001378972.1		c.-620_-613delCACACACA	5_prime_UTR	Exon 1 of 5	NP_001365901.1	P08172

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRM2	ENST00000680005.1	MANE Select	c.-508_-501delCACACACA	5_prime_UTR	Exon 1 of 4	ENSP00000505686.1	P08172
CHRM2	ENST00000445907.6	TSL:1	c.-430_-423delCACACACA	5_prime_UTR	Exon 1 of 3	ENSP00000399745.2	P08172
ENSG00000234352	ENST00000439694.6	TSL:1	n.656-82863_656-82856delTGTGTGTG	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000603

AC:

AN:

149266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000990

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00510

AC:

AN:

196

Hom.:

AF XY:

0.00610

AC XY:

AN XY:

164

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00575

AC:

AN:

174

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000603

AC:

AN:

149372

Hom.:

Cov.:

AF XY:

0.0000824

AC XY:

AN XY:

72804

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40802

American (AMR)

AF:

0.00

AC:

AN:

15032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

4928

South Asian (SAS)

AF:

0.00

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.0000990

AC:

AN:

10104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

67124

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Splicing

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