NM_003307.4:c.2263C>A

Variant names:

• chr21-44400313-C-A
• rs35288229
• NM_003307.4:c.2263C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003307.4(TRPM2):​c.2263C>A​(p.Arg755Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: 0.113
• Publications: 13 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	NM_003307.4	MANE Select	c.2263C>A	p.Arg755Ser	missense	Exon 15 of 32	NP_003298.2
	TRPM2	NM_001320350.2		c.2263C>A	p.Arg755Ser	missense	Exon 15 of 33	NP_001307279.2
	TRPM2	NM_001433516.1		c.2263C>A	p.Arg755Ser	missense	Exon 16 of 33	NP_001420445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.2263C>A	p.Arg755Ser	missense	Exon 15 of 32	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.2263C>A	p.Arg755Ser	missense	Exon 15 of 33	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.2263C>A	p.Arg755Ser	missense	Exon 16 of 33	ENSP00000300482.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249314 AF XY: 0.00000739

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460508 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726534

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111842

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.090	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.11
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.059	T
Polyphen		0.88	P
Vest4		0.77
MutPred		0.69		Loss of MoRF binding (P = 0.0554)
MVP		0.56
MPC		0.54
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.59
gMVP		0.62
Mutation Taster		=85/15	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: rs35288229; hg19: chr21-45820196;