21-44406579-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003307.4(TRPM2):c.2791-15C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,602,260 control chromosomes in the GnomAD database, including 445,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.71 (38674 hom., cov: 32)
  • Exomes 𝑓: 0.75 (407026 hom.)
• Consequence: TRPM2 NM_003307.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.150

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-44406579-C-A is Benign according to our data. Variant chr21-44406579-C-A is described in ClinVar as [Benign]. Clinvar id is 1265082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM2	NM_003307.4	c.2791-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397928.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM2	ENST00000397928.6	c.2791-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003307.4	P1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107695 AN: 151748 Hom.: 38674 Cov.: 32

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.730

GnomAD3 exomes AF: 0.728 AC: 172785 AN: 237226 Hom.: 63223 AF XY: 0.728 AC XY: 94196 AN XY: 129352

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.721

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.651

Gnomad FIN exome AF: 0.754

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.740

GnomAD4 exome AF: 0.748 AC: 1084843 AN: 1450394 Hom.: 407026 Cov.: 50 AF XY: 0.746 AC XY: 538158 AN XY: 721486

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.721

Gnomad4 EAS exome AF: 0.746

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.754

Gnomad4 NFE exome AF: 0.762

Gnomad4 OTH exome AF: 0.736

GnomAD4 genome AF: 0.709 AC: 107728 AN: 151866 Hom.: 38674 Cov.: 32 AF XY: 0.707 AC XY: 52502 AN XY: 74224

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.747

Gnomad4 ASJ AF: 0.718

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.766

Gnomad4 OTH AF: 0.729

Alfa AF: 0.731 Hom.: 8049

Bravo AF: 0.704

Asia WGS AF: 0.673 AC: 2344 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.0
Dann	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs1618355; hg19: chr21-45826462;