Genetic Variant NM_001006630.2:c.-502_-501dupCA (chr7-136868746-G-GCA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001006630.2(CHRM2):c.-502_-501dupCA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.020 ( 44 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: -0.214

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: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0199 (2969/149360) while in subpopulation AFR AF = 0.0486 (1984/40792). AF 95% confidence interval is 0.0469. There are 44 homozygotes in GnomAd4. There are 1342 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 gene

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.-502_-501dupCA	5_prime_UTR	Exon 1 of 4	NP_001006631.1	P08172
CHRM2	NM_001006627.3		c.-424_-423dupCA	5_prime_UTR	Exon 1 of 3	NP_001006628.1	A4D1Q0
CHRM2	NM_001378972.1		c.-614_-613dupCA	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.-502_-501dupCA	5_prime_UTR	Exon 1 of 4	ENSP00000505686.1	P08172
CHRM2	ENST00000445907.6	TSL:1	c.-424_-423dupCA	5_prime_UTR	Exon 1 of 3	ENSP00000399745.2	P08172
ENSG00000234352	ENST00000439694.6	TSL:1	n.656-82857_656-82856dupTG	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2946

AN:

149254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.0341

Gnomad AMR

AF:

0.00959

Gnomad ASJ

AF:

0.0102

Gnomad EAS

AF:

0.0132

Gnomad SAS

AF:

0.00469

Gnomad FIN

AF:

0.000792

Gnomad MID

AF:

0.00662

Gnomad NFE

AF:

0.00940

Gnomad OTH

AF:

0.0214

GnomAD4 exome

AF:

0.00510

AC:

AN:

196

Hom.:

Cov.:

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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0199

AC:

2969

AN:

149360

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1342

AN XY:

72792

show subpopulations

African (AFR)

AF:

0.0486

AC:

1984

AN:

40792

American (AMR)

AF:

0.00958

AC:

144

AN:

15032

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

AN:

3434

East Asian (EAS)

AF:

0.0136

AC:

AN:

4928

South Asian (SAS)

AF:

0.00470

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.000792

AC:

AN:

10106

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00940

AC:

631

AN:

67120

Other (OTH)

AF:

0.0217

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

126

252

378

504

630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00354

Hom.:

771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.21

Mutation Taster

=300/0

polymorphism

(source)

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