21-44401911-C-T

Variant names:

• chr21-44401911-C-T
• rs1785437
• NM_003307.4:c.2538+14C>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.2538+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,612,988 control chromosomes in the GnomAD database, including 455,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41860 hom., cov: 32)
  • Exomes 𝑓: 0.75 (413289 hom.)
• Consequence: TRPM2 NM_003307.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 8 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 (BayesDel_noAF=-0.97).
• BP6: Variant 21-44401911-C-T is Benign according to our data. Variant chr21-44401911-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM2	NM_003307.4	c.2538+14C>T		intron_variant	Intron 16 of 31	ENST00000397928.6	NP_003298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6	c.2538+14C>T		intron_variant	Intron 16 of 31	1	NM_003307.4	ENSP00000381023.1

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112593 AN: 151836 Hom.: 41845 Cov.: 32

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.750

GnomAD2 exomes AF: 0.737 AC: 184596 AN: 250366 AF XY: 0.735

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.723

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.753

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.746

GnomAD4 exome AF: 0.751 AC: 1097706 AN: 1461034 Hom.: 413289 Cov.: 49 AF XY: 0.749 AC XY: 544242 AN XY: 726802

African (AFR) AF: 0.700 AC: 23417 AN: 33476

American (AMR) AF: 0.729 AC: 32612 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 18853 AN: 26128

East Asian (EAS) AF: 0.751 AC: 29794 AN: 39696

South Asian (SAS) AF: 0.656 AC: 56563 AN: 86254

European-Finnish (FIN) AF: 0.754 AC: 39787 AN: 52784

Middle Eastern (MID) AF: 0.729 AC: 4205 AN: 5766

European-Non Finnish (NFE) AF: 0.762 AC: 847496 AN: 1111836

Other (OTH) AF: 0.745 AC: 44979 AN: 60380

GnomAD4 genome AF: 0.741 AC: 112662 AN: 151954 Hom.: 41860 Cov.: 32 AF XY: 0.739 AC XY: 54880 AN XY: 74260

African (AFR) AF: 0.701 AC: 29047 AN: 41436

American (AMR) AF: 0.759 AC: 11586 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2490 AN: 3470

East Asian (EAS) AF: 0.769 AC: 3957 AN: 5148

South Asian (SAS) AF: 0.652 AC: 3141 AN: 4820

European-Finnish (FIN) AF: 0.747 AC: 7895 AN: 10570

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52077 AN: 67928

Other (OTH) AF: 0.749 AC: 1580 AN: 2110

Alfa AF: 0.741 Hom.: 18436

Bravo AF: 0.741

Asia WGS AF: 0.687 AC: 2389 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.032
DANN	Benign	0.72
PhyloP100		-1.1
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: rs1785437; hg19: chr21-45821794;