chr21-44364274-G-T

Position:

• chr21-44364274-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003307.4(TRPM2):​c.415G>T​(p.Val139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073958725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM2	NM_003307.4	c.415G>T	p.Val139Leu	missense_variant	3/32	ENST00000397928.6	NP_003298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6	c.415G>T	p.Val139Leu	missense_variant	3/32	1	NM_003307.4	ENSP00000381023.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.415G>T (p.V139L) alteration is located in exon 3 (coding exon 3) of the TRPM2 gene. This alteration results from a G to T substitution at nucleotide position 415, causing the valine (V) at amino acid position 139 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T;T;T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	.;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;M;.;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.77	N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.72	T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.10	B;.;B;P;.
Vest4		0.13
MutPred		0.38		Loss of methylation at K138 (P = 0.0338);Loss of methylation at K138 (P = 0.0338);Loss of methylation at K138 (P = 0.0338);Loss of methylation at K138 (P = 0.0338);Loss of methylation at K138 (P = 0.0338);
MVP		0.14
MPC		0.14
ClinPred		0.096	T
GERP RS		2.4
Varity_R		0.099
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45784157;