chr21-44364207-G-A

Variant names:

• chr21-44364207-G-A
• rs45479791
• NM_003307.4:c.348G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003307.4(TRPM2):​c.348G>A​(p.Lys116Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,246 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (13 hom.)
• Consequence: TRPM2 NM_003307.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.143
• 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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 21-44364207-G-A is Benign according to our data. Variant chr21-44364207-G-A is described in ClinVar as Benign. ClinVar VariationId is 785673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.143 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00765 (1165/152368) while in subpopulation AFR AF = 0.0267 (1109/41582). AF 95% confidence interval is 0.0254. There are 10 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 gene

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.348G>A	p.Lys116Lys	synonymous	Exon 3 of 32	NP_003298.2	O94759-1
	TRPM2	NM_001320350.2		c.348G>A	p.Lys116Lys	synonymous	Exon 3 of 33	NP_001307279.2	E9PGK7
	TRPM2	NM_001433516.1		c.348G>A	p.Lys116Lys	synonymous	Exon 4 of 33	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.348G>A	p.Lys116Lys	synonymous	Exon 3 of 32	ENSP00000381023.1	O94759-1
	TRPM2	ENST00000397932.6	TSL:1	c.348G>A	p.Lys116Lys	synonymous	Exon 3 of 33	ENSP00000381026.2	E9PGK7
	TRPM2	ENST00000300482.9	TSL:1	c.348G>A	p.Lys116Lys	synonymous	Exon 4 of 33	ENSP00000300482.5	O94759-1

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1162 AN: 152250 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00199 AC: 500 AN: 251436 AF XY: 0.00143

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000737 AC: 1078 AN: 1461878 Hom.: 13 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 727242

African (AFR) AF: 0.0281 AC: 941 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112006

Other (OTH) AF: 0.00127 AC: 77 AN: 60396

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152368 Hom.: 10 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74504

African (AFR) AF: 0.0267 AC: 1109 AN: 41582

American (AMR) AF: 0.00255 AC: 39 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00288 Hom.: 9

Bravo AF: 0.00863

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	-0.73
CADD	Benign	5.3
DANN	Benign	0.72
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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: rs45479791; hg19: chr21-45784090;