21-44366826-G-A

Variant names:

• chr21-44366826-G-A
• rs45544142
• NM_003307.4:c.496G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003307.4(TRPM2):​c.496G>A​(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 1,613,640 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (236 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (227 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00900
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003167659).
• BP6: Variant 21-44366826-G-A is Benign according to our data. Variant chr21-44366826-G-A is described in ClinVar as Benign. ClinVar VariationId is 777642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.496G>A	p.Val166Ile	missense	Exon 4 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.496G>A	p.Val166Ile	missense	Exon 4 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.496G>A	p.Val166Ile	missense	Exon 5 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.496G>A	p.Val166Ile	missense	Exon 4 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.496G>A	p.Val166Ile	missense	Exon 4 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.496G>A	p.Val166Ile	missense	Exon 5 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4723 AN: 151788 Hom.: 236 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.00796 AC: 1998 AN: 250858 AF XY: 0.00597

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00315 AC: 4607 AN: 1461734 Hom.: 227 Cov.: 31 AF XY: 0.00278 AC XY: 2021 AN XY: 727168

African (AFR) AF: 0.109 AC: 3655 AN: 33474

American (AMR) AF: 0.00456 AC: 204 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26126

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39694

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5764

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1111966

Other (OTH) AF: 0.00647 AC: 391 AN: 60390

GnomAD4 genome AF: 0.0312 AC: 4733 AN: 151906 Hom.: 236 Cov.: 31 AF XY: 0.0296 AC XY: 2196 AN XY: 74234

African (AFR) AF: 0.107 AC: 4439 AN: 41364

American (AMR) AF: 0.0129 AC: 197 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5160

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67962

Other (OTH) AF: 0.0195 AC: 41 AN: 2104

Alfa AF: 0.0113 Hom.: 167

Bravo AF: 0.0353

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00967 AC: 1174

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.0
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.0090
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.033
Sift	Benign	0.45	T
Sift4G	Benign	0.45	T
Polyphen		0.039	B
Vest4		0.16
MVP		0.23
MPC		0.11
ClinPred		0.00063	T
GERP RS		2.3
Varity_R		0.063
gMVP		0.097
Mutation Taster		=100/0	polymorphism (auto)

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: rs45544142; hg19: chr21-45786709;