21-44391460-T-G

Variant names:

• chr21-44391460-T-G
• rs1556314
• NM_003307.4:c.1629T>G

Variant summary

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

The NM_001320350.2(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. 15/21 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 0.23 (4053 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32441 hom.)
• Consequence: TRPM2 NM_001320350.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 46 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320350.2. 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
	TRPM2	NM_003307.4	MANE Select	c.1629T>G	p.Asp543Glu	missense	Exon 11 of 32	NP_003298.2
	TRPM2	NM_001320350.2		c.1629T>G	p.Asp543Glu	missense	Exon 11 of 33	NP_001307279.2
	TRPM2	NM_001433516.1		c.1629T>G	p.Asp543Glu	missense	Exon 12 of 33	NP_001420445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.1629T>G	p.Asp543Glu	missense	Exon 11 of 32	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.1629T>G	p.Asp543Glu	missense	Exon 11 of 33	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.1629T>G	p.Asp543Glu	missense	Exon 12 of 33	ENSP00000300482.5

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

GnomAD2 exomes AF: 0.208 AC: 51583 AN: 247730 AF XY: 0.202

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 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

African (AFR) AF: 0.298 AC: 9976 AN: 33468

American (AMR) AF: 0.238 AC: 10647 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4551 AN: 26134

East Asian (EAS) AF: 0.152 AC: 6028 AN: 39696

South Asian (SAS) AF: 0.171 AC: 14763 AN: 86244

European-Finnish (FIN) AF: 0.261 AC: 13716 AN: 52470

Middle Eastern (MID) AF: 0.198 AC: 1118 AN: 5642

European-Non Finnish (NFE) AF: 0.208 AC: 230738 AN: 1111902

Other (OTH) AF: 0.204 AC: 12339 AN: 60364

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

African (AFR) AF: 0.288 AC: 11940 AN: 41490

American (AMR) AF: 0.213 AC: 3254 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3468

East Asian (EAS) AF: 0.149 AC: 771 AN: 5158

South Asian (SAS) AF: 0.165 AC: 795 AN: 4820

European-Finnish (FIN) AF: 0.274 AC: 2900 AN: 10592

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13557 AN: 68008

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.205 Hom.: 12752

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 v4.9

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
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.10
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
MutPred		0.32		Loss of helix (P = 0.0376)
MPC		0.13
ClinPred		0.0021	T
GERP RS		2.8
Varity_R		0.052
gMVP		0.094
Mutation Taster		=100/0	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: rs1556314; hg19: chr21-45811343; COSMIC: COSV55969202;