2-233945896-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024080.5(TRPM8):c.740G>C(p.Arg247Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0462 in 1,613,728 control chromosomes in the GnomAD database, including 1,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (163 hom., cov: 33)
  • Exomes 𝑓: 0.047 (1814 hom.)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.16

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030798316).
• BP6: Variant 2-233945896-G-C is Benign according to our data. Variant chr2-233945896-G-C is described in ClinVar as [Benign]. Clinvar id is 1246736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM8	NM_024080.5	c.740G>C	p.Arg247Thr	missense_variant	7/26	ENST00000324695.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM8	ENST00000324695.9	c.740G>C	p.Arg247Thr	missense_variant	7/26	1	NM_024080.5	P1
TRPM8	ENST00000444298.5	c.740G>C	p.Arg247Thr	missense_variant, NMD_transcript_variant	7/25	1
TRPM8	ENST00000433712.6	c.17G>C	p.Arg6Thr	missense_variant	7/24	5

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6238 AN: 152094 Hom.: 158 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0734

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0500 AC: 12564 AN: 251322 Hom.: 379 AF XY: 0.0479 AC XY: 6504 AN XY: 135814

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0449

Gnomad EAS exome AF: 0.0711

Gnomad SAS exome AF: 0.0432

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0468 AC: 68383 AN: 1461516 Hom.: 1814 Cov.: 30 AF XY: 0.0464 AC XY: 33719 AN XY: 727086

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.0966

Gnomad4 ASJ exome AF: 0.0457

Gnomad4 EAS exome AF: 0.0769

Gnomad4 SAS exome AF: 0.0424

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0411 AC: 6250 AN: 152212 Hom.: 163 Cov.: 33 AF XY: 0.0407 AC XY: 3030 AN XY: 74410

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0742

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.0710

Gnomad4 SAS AF: 0.0406

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0456 Hom.: 141

Bravo AF: 0.0458

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0490 AC: 189

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.0512 AC: 440

ExAC AF: 0.0470 AC: 5707

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.0449

EpiControl AF: 0.0421

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2019

This variant is associated with the following publications: (PMID: 27421018) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.057	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.019	D;D
Polyphen		0.45	P;.
Vest4		0.47
MPC		0.40
ClinPred		0.042	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs13004520; hg19: chr2-234854540; COSMIC: COSV61221178; COSMIC: COSV61221178;