NM_003307.4:c.3147-20T>C

Variant names:

• chr21-44417907-T-C
• rs1785452
• NM_003307.4:c.3147-20T>C

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.3147-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,602,140 control chromosomes in the GnomAD database, including 447,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38164 hom., cov: 33)
  • Exomes 𝑓: 0.75 (409038 hom.)
• Consequence: TRPM2 NM_003307.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.507
• Publications: 12 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 21-44417907-T-C is Benign according to our data. Variant chr21-44417907-T-C is described in ClinVar as Benign. ClinVar VariationId is 1261780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.762 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.3147-20T>C		intron	N/A	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3147-20T>C		intron	N/A	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3147-20T>C		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.3147-20T>C		intron	N/A	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3147-20T>C		intron	N/A	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3147-20T>C		intron	N/A	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106573 AN: 151930 Hom.: 38154 Cov.: 33

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.722

GnomAD2 exomes AF: 0.737 AC: 179779 AN: 243952 AF XY: 0.736

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.776

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.802

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.750 AC: 1087032 AN: 1450092 Hom.: 409038 Cov.: 46 AF XY: 0.748 AC XY: 538627 AN XY: 720350

African (AFR) AF: 0.541 AC: 18005 AN: 33308

American (AMR) AF: 0.777 AC: 34414 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18575 AN: 25838

East Asian (EAS) AF: 0.769 AC: 30385 AN: 39506

South Asian (SAS) AF: 0.670 AC: 57557 AN: 85962

European-Finnish (FIN) AF: 0.758 AC: 37135 AN: 49018

Middle Eastern (MID) AF: 0.731 AC: 4192 AN: 5738

European-Non Finnish (NFE) AF: 0.761 AC: 842380 AN: 1106406

Other (OTH) AF: 0.740 AC: 44389 AN: 60006

GnomAD4 genome AF: 0.701 AC: 106631 AN: 152048 Hom.: 38164 Cov.: 33 AF XY: 0.701 AC XY: 52108 AN XY: 74314

African (AFR) AF: 0.547 AC: 22666 AN: 41444

American (AMR) AF: 0.770 AC: 11774 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2484 AN: 3472

East Asian (EAS) AF: 0.782 AC: 4042 AN: 5170

South Asian (SAS) AF: 0.666 AC: 3212 AN: 4820

European-Finnish (FIN) AF: 0.753 AC: 7966 AN: 10586

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52081 AN: 67950

Other (OTH) AF: 0.721 AC: 1523 AN: 2112

Alfa AF: 0.742 Hom.: 15867

Bravo AF: 0.696

Asia WGS AF: 0.687 AC: 2383 AN: 3468

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	1.2
DANN	Benign	0.46
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1785452; hg19: chr21-45837790;