2-233983483-T-C

Variant names:

• chr2-233983483-T-C
• rs4663995
• NM_024080.5:c.2761+259T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024080.5(TRPM8):​c.2761+259T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 456,912 control chromosomes in the GnomAD database, including 139,365 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 0.78 (47014 hom., cov: 33)
  • Exomes 𝑓: 0.77 (92351 hom.)
• Consequence: TRPM8 NM_024080.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.72
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM8	NM_024080.5	c.2761+259T>C		intron_variant	Intron 20 of 25	ENST00000324695.9	NP_076985.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM8	ENST00000324695.9	c.2761+259T>C		intron_variant	Intron 20 of 25	1	NM_024080.5	ENSP00000323926.4

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119006 AN: 152068 Hom.: 46974 Cov.: 33

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.788

GnomAD4 exome AF: 0.770 AC: 234519 AN: 304726 Hom.: 92351 AF XY: 0.751 AC XY: 121457 AN XY: 161738

African (AFR) AF: 0.763 AC: 6476 AN: 8488

American (AMR) AF: 0.718 AC: 9959 AN: 13878

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 6966 AN: 8372

East Asian (EAS) AF: 0.589 AC: 9415 AN: 15992

South Asian (SAS) AF: 0.547 AC: 23472 AN: 42872

European-Finnish (FIN) AF: 0.832 AC: 23311 AN: 28010

Middle Eastern (MID) AF: 0.828 AC: 1118 AN: 1350

European-Non Finnish (NFE) AF: 0.832 AC: 141049 AN: 169600

Other (OTH) AF: 0.789 AC: 12753 AN: 16164

GnomAD4 genome AF: 0.783 AC: 119102 AN: 152186 Hom.: 47014 Cov.: 33 AF XY: 0.775 AC XY: 57686 AN XY: 74402

African (AFR) AF: 0.754 AC: 31280 AN: 41506

American (AMR) AF: 0.742 AC: 11343 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2868 AN: 3472

East Asian (EAS) AF: 0.573 AC: 2972 AN: 5184

South Asian (SAS) AF: 0.540 AC: 2601 AN: 4820

European-Finnish (FIN) AF: 0.841 AC: 8910 AN: 10596

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56418 AN: 68008

Other (OTH) AF: 0.784 AC: 1655 AN: 2110

Alfa AF: 0.811 Hom.: 154745

Bravo AF: 0.781

Asia WGS AF: 0.552 AC: 1920 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.078
DANN	Benign	0.36
PhyloP100		-3.7
Mutation Taster		=100/0	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: rs4663995; hg19: chr2-234892127;