2-233945906-G-C

Variant names:

• chr2-233945906-G-C
• rs11562975
• NM_024080.5:c.750G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_024080.5(TRPM8):​c.750G>C​(p.Leu250Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,926 control chromosomes in the GnomAD database, including 10,812 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 0.095 (931 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9881 hom.)
• Consequence: TRPM8 NM_024080.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298

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]

ENSG00000237581 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.298 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM8	NM_024080.5	c.750G>C	p.Leu250Leu	synonymous_variant	Exon 7 of 26	ENST00000324695.9	NP_076985.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM8	ENST00000324695.9	c.750G>C	p.Leu250Leu	synonymous_variant	Exon 7 of 26	1	NM_024080.5	ENSP00000323926.4
TRPM8	ENST00000444298.5	n.750G>C		non_coding_transcript_exon_variant	Exon 7 of 25	1		ENSP00000396745.1
TRPM8	ENST00000433712.6	c.27G>C	p.Leu9Leu	synonymous_variant	Exon 7 of 24	5		ENSP00000404423.3
ENSG00000237581	ENST00000455991.1	n.*240C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0949 AC: 14427 AN: 152068 Hom.: 926 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.0890

GnomAD3 exomes AF: 0.131 AC: 32954 AN: 251348 Hom.: 2840 AF XY: 0.130 AC XY: 17623 AN XY: 135844

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.216

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0974

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.108 AC: 158263 AN: 1461740 Hom.: 9881 Cov.: 32 AF XY: 0.109 AC XY: 79535 AN XY: 727190

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0996

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0949 AC: 14442 AN: 152186 Hom.: 931 Cov.: 32 AF XY: 0.100 AC XY: 7468 AN XY: 74390

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0994

Gnomad4 OTH AF: 0.0933

Alfa AF: 0.0897 Hom.: 229

Bravo AF: 0.0938

Asia WGS AF: 0.227 AC: 789 AN: 3478

EpiCase AF: 0.0868

EpiControl AF: 0.0904

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.1
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs11562975; hg19: chr2-234854550; COSMIC: COSV61222127; COSMIC: COSV61222127;