21-44366787-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003307.4(TRPM2):c.457G>A(p.Val153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,613,816 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (25 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006235808).
• BP6: Variant 21-44366787-G-A is Benign according to our data. Variant chr21-44366787-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 719307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM2	NM_003307.4	c.457G>A	p.Val153Met	missense_variant	4/32	ENST00000397928.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM2	ENST00000397928.6	c.457G>A	p.Val153Met	missense_variant	4/32	1	NM_003307.4	P1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 530 AN: 151872 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00328 AC: 825 AN: 251324 Hom.: 2 AF XY: 0.00321 AC XY: 436 AN XY: 135862

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00466 AC: 6813 AN: 1461826 Hom.: 25 Cov.: 31 AF XY: 0.00457 AC XY: 3324 AN XY: 727214

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00564

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00349 AC: 530 AN: 151990 Hom.: 2 Cov.: 31 AF XY: 0.00308 AC XY: 229 AN XY: 74286

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00528 Hom.: 7

Bravo AF: 0.00321

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00340 AC: 413

EpiCase AF: 0.00480

EpiControl AF: 0.00480

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.81
DEOGEN2	Benign	0.27	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.93	P;P;D;.
Vest4		0.23
MVP		0.12
MPC		0.16
ClinPred		0.0057	T
GERP RS		-1.4
Varity_R		0.071
gMVP		0.23

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: rs146154065; hg19: chr21-45786670; COSMIC: COSV99038950; COSMIC: COSV99038950;