chr21-44366826-G-A

Position:

• chr21-44366826-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003307.4(TRPM2):​c.496G>A​(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 1,613,640 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.031 (236 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (227 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003167659).
• BP6: Variant 21-44366826-G-A is Benign according to our data. Variant chr21-44366826-G-A is described in ClinVar as [Benign]. Clinvar id is 777642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM2	NM_003307.4	c.496G>A	p.Val166Ile	missense_variant	4/32	ENST00000397928.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM2	ENST00000397928.6	c.496G>A	p.Val166Ile	missense_variant	4/32	1	NM_003307.4	P1
TRPM2	ENST00000397932.6	c.496G>A	p.Val166Ile	missense_variant	4/33	1
TRPM2	ENST00000300482.9	c.496G>A	p.Val166Ile	missense_variant	5/33	1		P1
TRPM2	ENST00000300481.13	c.496G>A	p.Val166Ile	missense_variant	4/32	1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4723 AN: 151788 Hom.: 236 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.00796 AC: 1998 AN: 250858 Hom.: 107 AF XY: 0.00597 AC XY: 809 AN XY: 135618

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00315 AC: 4607 AN: 1461734 Hom.: 227 Cov.: 31 AF XY: 0.00278 AC XY: 2021 AN XY: 727168

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.0312 AC: 4733 AN: 151906 Hom.: 236 Cov.: 31 AF XY: 0.0296 AC XY: 2196 AN XY: 74234

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0195

Alfa AF: 0.00545 Hom.: 55

Bravo AF: 0.0353

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00967 AC: 1174

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.0
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.46	.;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.039	B;B;B;.
Vest4		0.16
MVP		0.23
MPC		0.11
ClinPred		0.00063	T
GERP RS		2.3
Varity_R		0.063
gMVP		0.097

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: rs45544142; hg19: chr21-45786709;