21-44424718-C-T

Variant names:

• chr21-44424718-C-T
• rs13050999
• NM_003307.4:c.3550-134C>T

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.3550-134C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 546,016 control chromosomes in the GnomAD database, including 110,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25456 hom., cov: 30)
  • Exomes 𝑓: 0.65 (85393 hom.)
• Consequence: TRPM2 NM_003307.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-44424718-C-T is Benign according to our data. Variant chr21-44424718-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 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.3550-134C>T		intron	N/A	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3700-134C>T		intron	N/A	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3550-134C>T		intron	N/A	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.3550-134C>T		intron	N/A	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3700-134C>T		intron	N/A	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3550-134C>T		intron	N/A	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81577 AN: 151446 Hom.: 25461 Cov.: 30

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.571

GnomAD4 exome AF: 0.651 AC: 256677 AN: 394450 Hom.: 85393 AF XY: 0.649 AC XY: 132098 AN XY: 203664

African (AFR) AF: 0.191 AC: 1948 AN: 10178

American (AMR) AF: 0.581 AC: 6947 AN: 11962

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 6993 AN: 11114

East Asian (EAS) AF: 0.622 AC: 15432 AN: 24820

South Asian (SAS) AF: 0.521 AC: 12966 AN: 24908

European-Finnish (FIN) AF: 0.685 AC: 17826 AN: 26018

Middle Eastern (MID) AF: 0.574 AC: 1141 AN: 1988

European-Non Finnish (NFE) AF: 0.687 AC: 179709 AN: 261528

Other (OTH) AF: 0.625 AC: 13715 AN: 21934

GnomAD4 genome AF: 0.538 AC: 81575 AN: 151566 Hom.: 25456 Cov.: 30 AF XY: 0.540 AC XY: 39988 AN XY: 74074

African (AFR) AF: 0.195 AC: 8054 AN: 41250

American (AMR) AF: 0.604 AC: 9211 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2180 AN: 3468

East Asian (EAS) AF: 0.693 AC: 3552 AN: 5124

South Asian (SAS) AF: 0.527 AC: 2535 AN: 4806

European-Finnish (FIN) AF: 0.684 AC: 7195 AN: 10514

Middle Eastern (MID) AF: 0.531 AC: 154 AN: 290

European-Non Finnish (NFE) AF: 0.691 AC: 46899 AN: 67858

Other (OTH) AF: 0.571 AC: 1199 AN: 2098

Alfa AF: 0.631 Hom.: 5959

Bravo AF: 0.518

Asia WGS AF: 0.546 AC: 1899 AN: 3478

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.8
DANN	Benign	0.71
PhyloP100		1.8
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: rs13050999; hg19: chr21-45844601; COSMIC: COSV55967662; COSMIC: COSV55967662;