2-233996434-C-T

Variant names:

• chr2-233996434-C-T
• rs11563208
• NM_024080.5:c.3048C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_024080.5(TRPM8):​c.3048C>T​(p.Ile1016Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,750 control chromosomes in the GnomAD database, including 58,153 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 0.22 (4384 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53769 hom.)
• Consequence: TRPM8 NM_024080.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 21 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.351 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

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.3048C>T	p.Ile1016Ile	synonymous	Exon 22 of 26	NP_076985.4
	TRPM8	NM_001397606.1		c.3048C>T	p.Ile1016Ile	synonymous	Exon 22 of 22	NP_001384535.1
	TRPM8	NM_001397607.1		c.2898C>T	p.Ile966Ile	synonymous	Exon 21 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.3048C>T	p.Ile1016Ile	synonymous	Exon 22 of 26	ENSP00000323926.4	Q7Z2W7-1
	TRPM8	ENST00000439148.1	TSL:1	n.*274C>T		non_coding_transcript_exon	Exon 4 of 8	ENSP00000390609.1	H7BZP4
	TRPM8	ENST00000444298.5	TSL:1	n.*1997C>T		non_coding_transcript_exon	Exon 21 of 25	ENSP00000396745.1	F8WD55

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33737 AN: 151996 Hom.: 4375 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.248 AC: 62449 AN: 251374 AF XY: 0.244

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0845

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.265 AC: 387621 AN: 1461636 Hom.: 53769 Cov.: 35 AF XY: 0.263 AC XY: 191161 AN XY: 727146

African (AFR) AF: 0.103 AC: 3456 AN: 33476

American (AMR) AF: 0.382 AC: 17057 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5415 AN: 26130

East Asian (EAS) AF: 0.106 AC: 4203 AN: 39696

South Asian (SAS) AF: 0.178 AC: 15341 AN: 86234

European-Finnish (FIN) AF: 0.214 AC: 11409 AN: 53416

Middle Eastern (MID) AF: 0.236 AC: 1359 AN: 5768

European-Non Finnish (NFE) AF: 0.283 AC: 314479 AN: 1111822

Other (OTH) AF: 0.247 AC: 14902 AN: 60386

GnomAD4 genome AF: 0.222 AC: 33754 AN: 152114 Hom.: 4384 Cov.: 32 AF XY: 0.218 AC XY: 16177 AN XY: 74340

African (AFR) AF: 0.111 AC: 4611 AN: 41504

American (AMR) AF: 0.324 AC: 4948 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3464

East Asian (EAS) AF: 0.0839 AC: 435 AN: 5182

South Asian (SAS) AF: 0.179 AC: 862 AN: 4814

European-Finnish (FIN) AF: 0.188 AC: 1990 AN: 10564

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19226 AN: 67988

Other (OTH) AF: 0.221 AC: 467 AN: 2114

Alfa AF: 0.263 Hom.: 11191

Bravo AF: 0.230

Asia WGS AF: 0.113 AC: 393 AN: 3478

EpiCase AF: 0.284

EpiControl AF: 0.286

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		-0.35
Mutation Taster		=96/4	polymorphism (auto)

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: rs11563208; hg19: chr2-234905078; COSMIC: COSV61223462;