21-44418450-C-T

Variant names:

• chr21-44418450-C-T
• rs137972023
• NM_003307.4:c.3356C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_003307.4(TRPM2):​c.3356C>T​(p.Ala1119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52
• Publications: 5 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02047968).
• BP6: Variant 21-44418450-C-T is Benign according to our data. Variant chr21-44418450-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3770637.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3356C>T	p.Ala1119Val	missense	Exon 22 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3356C>T	p.Ala1119Val	missense	Exon 22 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3356C>T	p.Ala1119Val	missense	Exon 23 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.3356C>T	p.Ala1119Val	missense	Exon 22 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3356C>T	p.Ala1119Val	missense	Exon 22 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3356C>T	p.Ala1119Val	missense	Exon 23 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000597 AC: 150 AN: 251198 AF XY: 0.000516

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000766 AC: 1119 AN: 1461720 Hom.: 0 Cov.: 32 AF XY: 0.000705 AC XY: 513 AN XY: 727152

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000336 AC: 15 AN: 44708

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53338

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

European-Non Finnish (NFE) AF: 0.000923 AC: 1026 AN: 1111958

Other (OTH) AF: 0.000762 AC: 46 AN: 60392

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74440

African (AFR) AF: 0.000217 AC: 9 AN: 41522

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000683 Hom.: 1

Bravo AF: 0.000419

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000741 AC: 90

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.081
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.12	B
Vest4		0.26
MVP		0.63
MPC		0.16
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.070
gMVP		0.27
Mutation Taster		=87/13	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: rs137972023; hg19: chr21-45838333; COSMIC: COSV55971279; COSMIC: COSV55971279;