rs1556314

Positions:

• chr21-44391460-T-G
• chr21-44391460-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003307.4(TRPM2):​c.1629T>G​(p.Asp543Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,776 control chromosomes in the GnomAD database, including 36,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4053 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32441 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105

Genes affected

TRPM2 (HGNC:12339): (transient receptor potential cation channel subfamily M member 2) The protein encoded by this gene forms a tetrameric cation channel that is permeable to calcium, sodium, and potassium and is regulated by free intracellular ADP-ribose. The encoded protein is activated by oxidative stress and confers susceptibility to cell death. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. Additional transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2016]

TRPM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042249262).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM2	NM_003307.4	c.1629T>G	p.Asp543Glu	missense_variant	11/32	ENST00000397928.6	NP_003298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6	c.1629T>G	p.Asp543Glu	missense_variant	11/32	1	NM_003307.4	ENSP00000381023.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34367 AN: 152026 Hom.: 4031 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.208 AC: 51583 AN: 247730 Hom.: 5703 AF XY: 0.202 AC XY: 27233 AN XY: 134510

Gnomad AFR exome AF: 0.288

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.208 AC: 303876 AN: 1460632 Hom.: 32441 Cov.: 34 AF XY: 0.206 AC XY: 149863 AN XY: 726582

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.226 AC: 34448 AN: 152144 Hom.: 4053 Cov.: 32 AF XY: 0.227 AC XY: 16843 AN XY: 74358

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.185

Alfa AF: 0.197 Hom.: 5625

Bravo AF: 0.227

TwinsUK AF: 0.197 AC: 732

ALSPAC AF: 0.217 AC: 837

ESP6500AA AF: 0.285 AC: 1254

ESP6500EA AF: 0.200 AC: 1717

ExAC AF: 0.205 AC: 24908

Asia WGS AF: 0.168 AC: 586 AN: 3476

EpiCase AF: 0.192

EpiControl AF: 0.190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.11
DANN	Benign	0.39
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.44	.;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N;N;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.043
MutPred		0.32		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MPC		0.13
ClinPred		0.0021	T
GERP RS		2.8
Varity_R		0.052
gMVP		0.094

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556314; hg19: chr21-45811343; COSMIC: COSV55969202;