21-44400313-C-T

Variant names:

• chr21-44400313-C-T
• rs35288229
• NM_003307.4:c.2263C>T

Variant summary

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

The NM_003307.4(TRPM2):​c.2263C>T​(p.Arg755Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,612,656 control chromosomes in the GnomAD database, including 2,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.041 (188 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2242 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 13 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=0.003799945).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003307.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	NM_003307.4	MANE Select	c.2263C>T	p.Arg755Cys	missense	Exon 15 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.2263C>T	p.Arg755Cys	missense	Exon 15 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.2263C>T	p.Arg755Cys	missense	Exon 16 of 33	NP_001420445.1	O94759-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.2263C>T	p.Arg755Cys	missense	Exon 15 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.2263C>T	p.Arg755Cys	missense	Exon 15 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.2263C>T	p.Arg755Cys	missense	Exon 16 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6198 AN: 152156 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0409 AC: 10192 AN: 249314 AF XY: 0.0416

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0928

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0521 AC: 76037 AN: 1460382 Hom.: 2242 Cov.: 32 AF XY: 0.0515 AC XY: 37409 AN XY: 726484

African (AFR) AF: 0.00759 AC: 254 AN: 33476

American (AMR) AF: 0.0234 AC: 1046 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 781 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0196 AC: 1688 AN: 86192

European-Finnish (FIN) AF: 0.0941 AC: 4924 AN: 52314

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5766

European-Non Finnish (NFE) AF: 0.0582 AC: 64706 AN: 1111766

Other (OTH) AF: 0.0417 AC: 2519 AN: 60364

GnomAD4 genome AF: 0.0407 AC: 6198 AN: 152274 Hom.: 188 Cov.: 33 AF XY: 0.0409 AC XY: 3043 AN XY: 74466

African (AFR) AF: 0.00982 AC: 408 AN: 41548

American (AMR) AF: 0.0280 AC: 429 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4826

European-Finnish (FIN) AF: 0.103 AC: 1093 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0579 AC: 3937 AN: 68026

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0519 Hom.: 490

Bravo AF: 0.0331

TwinsUK AF: 0.0545 AC: 202

ALSPAC AF: 0.0631 AC: 243

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0548 AC: 471

ExAC AF: 0.0404 AC: 4898

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0522

EpiControl AF: 0.0507

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.11
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.68
MPC		0.69
ClinPred		0.055	T
GERP RS		1.7
Varity_R		0.63
gMVP		0.57
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35288229; hg19: chr21-45820196; COSMIC: COSV107362353;