21-44417954-C-G

Variant names:

• chr21-44417954-C-G
• rs201748864
• NM_003307.4:c.3174C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003307.4(TRPM2):​c.3174C>G​(p.His1058Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000285 in 1,612,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1058P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054623306).

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.3174C>G	p.His1058Gln	missense	Exon 21 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3174C>G	p.His1058Gln	missense	Exon 21 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3174C>G	p.His1058Gln	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.3174C>G	p.His1058Gln	missense	Exon 21 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3174C>G	p.His1058Gln	missense	Exon 21 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3174C>G	p.His1058Gln	missense	Exon 22 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000720 AC: 18 AN: 249866 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000292 AC: 426 AN: 1460430 Hom.: 0 Cov.: 36 AF XY: 0.000282 AC XY: 205 AN XY: 726558

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52088

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

European-Non Finnish (NFE) AF: 0.000371 AC: 412 AN: 1111936

Other (OTH) AF: 0.000166 AC: 10 AN: 60380

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.000327 AC: 5 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.000227

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	N
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.13
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.45
MutPred		0.29		Gain of helix (P = 0.132)
MVP		0.56
MPC		0.44
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.61
gMVP		0.52
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201748864; hg19: chr21-45837837;