7-136868746-GCACACACACACACACA-GCACACACACACA

Variant names:

• chr7-136868746-GCACA-G
• rs35916399
• NM_001006630.2:c.-504_-501delCACA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001006630.2(CHRM2):​c.-504_-501delCACA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 149,120 control chromosomes in the GnomAD database, including 43 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (43 hom., cov: 0)
  • Exomes 𝑓: 0.041 (0 hom.)
• Consequence: CHRM2 NM_001006630.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.95
• Publications: 3 publications found

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]

ENSG00000234352 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-136868746-GCACA-G is Benign according to our data. Variant chr7-136868746-GCACA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1316263.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2246/148926) while in subpopulation AFR AF = 0.0461 (1880/40768). AF 95% confidence interval is 0.0444. There are 43 homozygotes in GnomAd4. There are 1087 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	NM_001006630.2	MANE Select	c.-504_-501delCACA		5_prime_UTR	Exon 1 of 4	NP_001006631.1	P08172
	CHRM2	NM_001006627.3		c.-426_-423delCACA		5_prime_UTR	Exon 1 of 3	NP_001006628.1	A4D1Q0
	CHRM2	NM_001378972.1		c.-616_-613delCACA		5_prime_UTR	Exon 1 of 5	NP_001365901.1	P08172

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM2	ENST00000680005.1	MANE Select	c.-504_-501delCACA		5_prime_UTR	Exon 1 of 4	ENSP00000505686.1	P08172
	CHRM2	ENST00000445907.6	TSL:1	c.-426_-423delCACA		5_prime_UTR	Exon 1 of 3	ENSP00000399745.2	P08172
	ENSG00000234352	ENST00000439694.6	TSL:1	n.656-82859_656-82856delTGTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2237 AN: 148830 Hom.: 43 Cov.: 0

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00384

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0132

GnomAD4 exome AF: 0.0412 AC: 8 AN: 194 Hom.: 0 AF XY: 0.0370 AC XY: 6 AN XY: 162

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0465 AC: 8 AN: 172

Other (OTH) AF: 0.00 AC: 0 AN: 8

⚠️ 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.

GnomAD4 genome AF: 0.0151 AC: 2246 AN: 148926 Hom.: 43 Cov.: 0 AF XY: 0.0150 AC XY: 1087 AN XY: 72560

African (AFR) AF: 0.0461 AC: 1880 AN: 40768

American (AMR) AF: 0.00581 AC: 87 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3428

East Asian (EAS) AF: 0.0185 AC: 91 AN: 4916

South Asian (SAS) AF: 0.00385 AC: 18 AN: 4674

European-Finnish (FIN) AF: 0.00152 AC: 15 AN: 9896

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.00187 AC: 125 AN: 67014

Other (OTH) AF: 0.0131 AC: 27 AN: 2066

Alfa AF: 0.000917 Hom.: 771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs35916399; hg19: chr7-136553493;