Variant chr2-233945896-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.16

Variant links:

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]

TRPM8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
TRPM8	NM_024080.5 linkuse as main transcript	c.740G>C	p.Arg247Thr	missense_variant	7/26	ENST00000324695.9	NP_076985.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM8	ENST00000324695.9 linkuse as main transcript	c.740G>C	p.Arg247Thr	missense_variant	7/26	1	NM_024080.5	ENSP00000323926	P1	Q7Z2W7-1
TRPM8	ENST00000444298.5 linkuse as main transcript	c.740G>C	p.Arg247Thr	missense_variant, NMD_transcript_variant	7/25	1		ENSP00000396745
TRPM8	ENST00000433712.6 linkuse as main transcript	c.17G>C	p.Arg6Thr	missense_variant	7/24	5		ENSP00000404423

Frequencies

GnomAD3 genomes

AF:

0.0410

AC:

6238

AN:

152094

Hom.:

158

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0464

AC XY:

33719

AN XY:

727086

show subpopulations

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.:

AF XY:

0.0407

AC XY:

3030

AN XY:

74410

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

0.057

P;P

PrimateAI

Benign

0.43

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over