21-44418749-C-T

Variant names:

• chr21-44418749-C-T
• rs1785467
• NM_003307.4:c.3461+194C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003307.4(TRPM2):​c.3461+194C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,146 control chromosomes in the GnomAD database, including 60,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.89 (60591 hom., cov: 32)
• Consequence: TRPM2 NM_003307.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.141
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-44418749-C-T is Benign according to our data. Variant chr21-44418749-C-T is described in ClinVar as Benign. ClinVar VariationId is 1245588.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 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.3461+194C>T		intron	N/A	NP_003298.2
	TRPM2	NM_001320350.2		c.3461+194C>T		intron	N/A	NP_001307279.2
	TRPM2	NM_001433516.1		c.3461+194C>T		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.3461+194C>T		intron	N/A	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.3461+194C>T		intron	N/A	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.3461+194C>T		intron	N/A	ENSP00000300482.5

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135600 AN: 152028 Hom.: 60549 Cov.: 32

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.898

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

GnomAD4 genome AF: 0.892 AC: 135701 AN: 152146 Hom.: 60591 Cov.: 32 AF XY: 0.892 AC XY: 66333 AN XY: 74390

African (AFR) AF: 0.938 AC: 38927 AN: 41518

American (AMR) AF: 0.861 AC: 13186 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 3021 AN: 3470

East Asian (EAS) AF: 0.942 AC: 4847 AN: 5144

South Asian (SAS) AF: 0.891 AC: 4302 AN: 4826

European-Finnish (FIN) AF: 0.858 AC: 9093 AN: 10598

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.874 AC: 59430 AN: 67968

Other (OTH) AF: 0.897 AC: 1893 AN: 2110

Alfa AF: 0.897 Hom.: 8062

Bravo AF: 0.893

Asia WGS AF: 0.915 AC: 3182 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.2
DANN	Benign	0.93
PhyloP100		-0.14
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: rs1785467; hg19: chr21-45838632;