2-233983483-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024080.5(TRPM8):​c.2761+259T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 305,112 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: 33)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: TRPM8 NM_024080.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.72
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

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.2761+259T>G		intron	N/A	NP_076985.4
	TRPM8	NM_001397606.1		c.2761+259T>G		intron	N/A	NP_001384535.1
	TRPM8	NM_001397607.1		c.2611+259T>G		intron	N/A	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.2761+259T>G		intron	N/A	ENSP00000323926.4	Q7Z2W7-1
	TRPM8	ENST00000439148.1	TSL:1	n.407+132T>G		intron	N/A	ENSP00000390609.1	H7BZP4
	TRPM8	ENST00000444298.5	TSL:1	n.*1710+259T>G		intron	N/A	ENSP00000396745.1	F8WD55

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000328 AC: 1 AN: 305112 Hom.: 0 AF XY: 0.00000618 AC XY: 1 AN XY: 161918

African (AFR) AF: 0.00 AC: 0 AN: 8496

American (AMR) AF: 0.00 AC: 0 AN: 13886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8382

East Asian (EAS) AF: 0.00 AC: 0 AN: 16032

South Asian (SAS) AF: 0.0000233 AC: 1 AN: 42918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 169804

Other (OTH) AF: 0.00 AC: 0 AN: 16184

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.067
DANN	Benign	0.44
PhyloP100		-3.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4663995;

hg19: chr2-234892127;