chr2-233955144-G-A

Variant names:

• chr2-233955144-G-A
• rs7593557
• NM_024080.5:c.1256G>A

Variant summary

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

The NM_024080.5(TRPM8):​c.1256G>A​(p.Ser419Asn) variant causes a missense change. The variant allele was found at a frequency of 0.101 in 1,613,196 control chromosomes in the GnomAD database, including 22,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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 (7390 hom., cov: 32)
  • Exomes 𝑓: 0.089 (14707 hom.)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 26 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]

ENSG00000237581 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7243624E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM8	NM_024080.5	MANE Select	c.1256G>A	p.Ser419Asn	missense	Exon 11 of 26	NP_076985.4
	TRPM8	NM_001397606.1		c.1256G>A	p.Ser419Asn	missense	Exon 11 of 22	NP_001384535.1
	TRPM8	NM_001397607.1		c.1106G>A	p.Ser369Asn	missense	Exon 10 of 25	NP_001384536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM8	ENST00000324695.9	TSL:1 MANE Select	c.1256G>A	p.Ser419Asn	missense	Exon 11 of 26	ENSP00000323926.4
	TRPM8	ENST00000444298.5	TSL:1	n.*535G>A		non_coding_transcript_exon	Exon 12 of 25	ENSP00000396745.1
	TRPM8	ENST00000444298.5	TSL:1	n.*535G>A		3_prime_UTR	Exon 12 of 25	ENSP00000396745.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33281 AN: 152068 Hom.: 7355 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0519

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.148 AC: 37194 AN: 251112 AF XY: 0.139

Gnomad AFR exome AF: 0.559

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.463

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0498

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0891 AC: 130135 AN: 1461010 Hom.: 14707 Cov.: 30 AF XY: 0.0905 AC XY: 65774 AN XY: 726856

African (AFR) AF: 0.563 AC: 18829 AN: 33416

American (AMR) AF: 0.153 AC: 6850 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 1765 AN: 26124

East Asian (EAS) AF: 0.458 AC: 18177 AN: 39676

South Asian (SAS) AF: 0.212 AC: 18289 AN: 86188

European-Finnish (FIN) AF: 0.0292 AC: 1560 AN: 53398

Middle Eastern (MID) AF: 0.0805 AC: 464 AN: 5766

European-Non Finnish (NFE) AF: 0.0509 AC: 56582 AN: 1111382

Other (OTH) AF: 0.126 AC: 7619 AN: 60344

GnomAD4 genome AF: 0.219 AC: 33377 AN: 152186 Hom.: 7390 Cov.: 32 AF XY: 0.218 AC XY: 16243 AN XY: 74414

African (AFR) AF: 0.551 AC: 22858 AN: 41474

American (AMR) AF: 0.159 AC: 2436 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3470

East Asian (EAS) AF: 0.459 AC: 2373 AN: 5168

South Asian (SAS) AF: 0.243 AC: 1172 AN: 4818

European-Finnish (FIN) AF: 0.0296 AC: 314 AN: 10622

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0519 AC: 3527 AN: 68010

Other (OTH) AF: 0.176 AC: 373 AN: 2116

Alfa AF: 0.107 Hom.: 9165

Bravo AF: 0.240

TwinsUK AF: 0.0564 AC: 209

ALSPAC AF: 0.0566 AC: 218

ESP6500AA AF: 0.530 AC: 2336

ESP6500EA AF: 0.0580 AC: 499

ExAC AF: 0.155 AC: 18770

Asia WGS AF: 0.365 AC: 1270 AN: 3478

EpiCase AF: 0.0508

EpiControl AF: 0.0487

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.074	T
MetaRNN	Benign	0.00017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.076
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.076
MPC		0.14
ClinPred		0.0030	T
GERP RS		6.0
Varity_R		0.033
gMVP		0.11
Mutation Taster		=99/1	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: rs7593557; hg19: chr2-234863788; COSMIC: COSV61220753;