rs4818917

Variant names:

• chr21-44379397-T-C
• rs4818917
• NM_003307.4:c.1215+200T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003307.4(TRPM2):​c.1215+200T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 151,894 control chromosomes in the GnomAD database, including 4,865 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4865 hom., cov: 32)
• Consequence: TRPM2 NM_003307.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.91
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	NM_003307.4	MANE Select	c.1215+200T>C		intron	N/A	NP_003298.2
	TRPM2	NM_001320350.2		c.1215+200T>C		intron	N/A	NP_001307279.2
	TRPM2	NM_001433516.1		c.1215+200T>C		intron	N/A	NP_001420445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.1215+200T>C		intron	N/A	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.1215+200T>C		intron	N/A	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.1215+200T>C		intron	N/A	ENSP00000300482.5

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36990 AN: 151776 Hom.: 4843 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.244 AC: 37073 AN: 151894 Hom.: 4865 Cov.: 32 AF XY: 0.243 AC XY: 18071 AN XY: 74246

African (AFR) AF: 0.345 AC: 14287 AN: 41390

American (AMR) AF: 0.222 AC: 3389 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3468

East Asian (EAS) AF: 0.150 AC: 771 AN: 5142

South Asian (SAS) AF: 0.168 AC: 808 AN: 4820

European-Finnish (FIN) AF: 0.275 AC: 2905 AN: 10554

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13650 AN: 67912

Other (OTH) AF: 0.195 AC: 412 AN: 2116

Alfa AF: 0.219 Hom.: 1447

Bravo AF: 0.247

Asia WGS AF: 0.173 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.26
PhyloP100		-2.9
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: rs4818917; hg19: chr21-45799280;