chr21-44418084-C-A

Variant names:

• chr21-44418084-C-A
• rs201505422
• NM_003307.4:c.3304C>A

Variant summary

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

The NM_003307.4(TRPM2):​c.3304C>A​(p.Pro1102Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,134 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.27

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]

TRPM2-AS (HGNC:50758): (TRPM2 antisense RNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM2	NM_003307.4	c.3304C>A	p.Pro1102Thr	missense_variant	Exon 21 of 32	ENST00000397928.6	NP_003298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6	c.3304C>A	p.Pro1102Thr	missense_variant	Exon 21 of 32	1	NM_003307.4	ENSP00000381023.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460134 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;T;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.46	T;T;T;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.65
MutPred		0.38		Loss of glycosylation at P1102 (P = 0.0189);Loss of glycosylation at P1102 (P = 0.0189);Loss of glycosylation at P1102 (P = 0.0189);.;
MVP		0.40
MPC		0.63
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.35
gMVP		0.48

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: rs201505422; hg19: chr21-45837967;