NM_003307.4:c.3304C>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1102S) has been classified as Uncertain significance.

• 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
• Publications: 0 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.3304C>A	p.Pro1102Thr	missense	Exon 21 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3304C>A	p.Pro1102Thr	missense	Exon 21 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3304C>A	p.Pro1102Thr	missense	Exon 22 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.3304C>A	p.Pro1102Thr	missense	Exon 21 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3304C>A	p.Pro1102Thr	missense	Exon 21 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3304C>A	p.Pro1102Thr	missense	Exon 22 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249462 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111722

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.23
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.38		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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs201505422; hg19: chr21-45837967;