NM_003307.4:c.3549+8C>T

Variant names:

• chr21-44423740-C-T
• rs367545571
• NM_003307.4:c.3549+8C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003307.4(TRPM2):​c.3549+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,598,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: TRPM2 NM_003307.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004870
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44423740-C-T is Benign according to our data. Variant chr21-44423740-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 726111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3549+8C>T		splice_region intron	N/A	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.3699+8C>T		splice_region intron	N/A	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.3549+8C>T		splice_region 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.3549+8C>T		splice_region intron	N/A	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.3699+8C>T		splice_region intron	N/A	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.3549+8C>T		splice_region intron	N/A	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000710 AC: 156 AN: 219664 AF XY: 0.000766

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.000536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000598

Gnomad NFE exome AF: 0.000998

Gnomad OTH exome AF: 0.000916

GnomAD4 exome AF: 0.000691 AC: 999 AN: 1445960 Hom.: 1 Cov.: 30 AF XY: 0.000689 AC XY: 495 AN XY: 718066

African (AFR) AF: 0.000150 AC: 5 AN: 33394

American (AMR) AF: 0.000547 AC: 23 AN: 42014

Ashkenazi Jewish (ASJ) AF: 0.000428 AC: 11 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.00103 AC: 86 AN: 83698

European-Finnish (FIN) AF: 0.0000803 AC: 4 AN: 49832

Middle Eastern (MID) AF: 0.00219 AC: 12 AN: 5468

European-Non Finnish (NFE) AF: 0.000727 AC: 805 AN: 1106692

Other (OTH) AF: 0.000885 AC: 53 AN: 59910

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74414

African (AFR) AF: 0.0000963 AC: 4 AN: 41530

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000532 Hom.: 1

Bravo AF: 0.000510

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.89
CADD	Benign	4.6
DANN	Benign	0.79
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.012
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: rs367545571; hg19: chr21-45843623;