21-44424868-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM2	NM_003307.4	c.3566A>G	p.Gln1189Arg	missense_variant	Exon 24 of 32	ENST00000397928.6	NP_003298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6	c.3566A>G	p.Gln1189Arg	missense_variant	Exon 24 of 32	1	NM_003307.4	ENSP00000381023.1

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

GnomAD3 exomes AF: 0.975 AC: 227429 AN: 233350 Hom.: 111014 AF XY: 0.979 AC XY: 124334 AN XY: 126982

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 SAS exome AF: 0.980

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

Gnomad4 AFR exome AF: 0.934

Gnomad4 AMR exome AF: 0.909

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 0.942

Gnomad4 SAS exome AF: 0.982

Gnomad4 FIN exome AF: 0.989

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.988

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

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.938

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 0.951

Gnomad4 SAS AF: 0.979

Gnomad4 FIN AF: 0.986

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.981

Alfa AF: 0.992 Hom.: 101303

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 v4.3

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;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.011	.;T;T;T
MetaRNN	Benign	5.7e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N;N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.71	N;N;N;N
REVEL	Benign	0.012
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.048
MPC		0.15
ClinPred		0.0040	T
GERP RS		-1.3
Varity_R		0.030
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs9978351; hg19: chr21-45844751;