21-44424868-A-G

Variant names:

• chr21-44424868-A-G
• rs9978351
• NM_003307.4:c.3566A>G

Variant summary

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

The NM_003307.4(TRPM2):​c.3566A>G​(p.Gln1189Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,604,358 control chromosomes in the GnomAD database, including 786,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.97 (71904 hom., cov: 29)
  • Exomes 𝑓: 0.99 (714908 hom.)
• Consequence: TRPM2 NM_003307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• Publications: 29 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 (MetaRNN=5.6996913E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.3566A>G	p.Gln1189Arg	missense	Exon 24 of 32	NP_003298.2
	TRPM2	NM_001320350.2		c.3716A>G	p.Gln1239Arg	missense	Exon 25 of 33	NP_001307279.2
	TRPM2	NM_001433516.1		c.3566A>G	p.Gln1189Arg	missense	Exon 25 of 33	NP_001420445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.3566A>G	p.Gln1189Arg	missense	Exon 24 of 32	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.3716A>G	p.Gln1239Arg	missense	Exon 25 of 33	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.3566A>G	p.Gln1189Arg	missense	Exon 25 of 33	ENSP00000300482.5

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147671 AN: 151952 Hom.: 71858 Cov.: 29

Gnomad AFR AF: 0.934

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.980

GnomAD2 exomes AF: 0.975 AC: 227429 AN: 233350 AF XY: 0.979

Gnomad AFR exome AF: 0.932

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 0.957

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.984

GnomAD4 exome AF: 0.992 AC: 1440631 AN: 1452288 Hom.: 714908 Cov.: 50 AF XY: 0.992 AC XY: 715994 AN XY: 721624

African (AFR) AF: 0.934 AC: 31122 AN: 33326

American (AMR) AF: 0.909 AC: 39680 AN: 43644

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 25873 AN: 25890

East Asian (EAS) AF: 0.942 AC: 37063 AN: 39330

South Asian (SAS) AF: 0.982 AC: 83097 AN: 84612

European-Finnish (FIN) AF: 0.989 AC: 51207 AN: 51784

Middle Eastern (MID) AF: 0.993 AC: 5091 AN: 5128

European-Non Finnish (NFE) AF: 1.00 AC: 1108251 AN: 1108616

Other (OTH) AF: 0.988 AC: 59247 AN: 59958

GnomAD4 genome AF: 0.972 AC: 147776 AN: 152070 Hom.: 71904 Cov.: 29 AF XY: 0.969 AC XY: 72044 AN XY: 74322

African (AFR) AF: 0.934 AC: 38723 AN: 41456

American (AMR) AF: 0.938 AC: 14338 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3470 AN: 3472

East Asian (EAS) AF: 0.951 AC: 4884 AN: 5138

South Asian (SAS) AF: 0.979 AC: 4695 AN: 4798

European-Finnish (FIN) AF: 0.986 AC: 10464 AN: 10610

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67924 AN: 67988

Other (OTH) AF: 0.981 AC: 2073 AN: 2114

Alfa AF: 0.988 Hom.: 134193

Bravo AF: 0.968

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.935 AC: 4113

ESP6500EA AF: 0.999 AC: 8585

ExAC AF: 0.976 AC: 117690

Asia WGS AF: 0.960 AC: 3337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.9
DANN	Benign	0.67
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.011	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.32
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.15
ClinPred		0.0040	T
GERP RS		-1.3
Varity_R		0.030
gMVP		0.15
Mutation Taster		=99/1	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: rs9978351; hg19: chr21-45844751; COSMIC: COSV107362068; COSMIC: COSV107362068;