2-233942716-C-A

Variant names:

• chr2-233942716-C-A
• rs762851956
• NM_024080.5:c.667C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_024080.5(TRPM8):​c.667C>A​(p.Arg223Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TRPM8 NM_024080.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

TRPM8 (HGNC:17961): (transient receptor potential cation channel subfamily M member 8) Predicted to enable ligand-gated calcium channel activity. Predicted to be involved in calcium ion transmembrane transport and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within several processes, including cellular calcium ion homeostasis; response to cold; and thermoception. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024080.5. 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
	TRPM8	NM_024080.5	MANE Select	c.667C>A	p.Arg223Arg	synonymous	Exon 6 of 26	NP_076985.4
	TRPM8	NM_001397606.1		c.667C>A	p.Arg223Arg	synonymous	Exon 6 of 22	NP_001384535.1
	TRPM8	NM_001397607.1		c.517C>A	p.Arg173Arg	synonymous	Exon 5 of 25	NP_001384536.1	A0A1L1Z857

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM8	ENST00000324695.9	TSL:1 MANE Select	c.667C>A	p.Arg223Arg	synonymous	Exon 6 of 26	ENSP00000323926.4	Q7Z2W7-1
	TRPM8	ENST00000355722.8	TSL:1	c.517C>A	p.Arg173Arg	synonymous	Exon 5 of 5	ENSP00000347956.4	A0A0C4DFT0
	TRPM8	ENST00000409625.1	TSL:1	c.436C>A	p.Arg146Arg	synonymous	Exon 5 of 5	ENSP00000386771.1	Q7Z2W7-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251486 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000455559), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	9.3
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762851956; hg19: chr2-234851360; COSMIC: COSV61221931; COSMIC: COSV61221931;