rs9978351

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-44424868-A-C
• chr21-44424868-A-G
• chr21-44424868-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003307.4(TRPM2):​c.3566A>C​(p.Gln1189Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09192103).

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>C	p.Gln1189Pro	missense	Exon 24 of 32	NP_003298.2
	TRPM2	NM_001320350.2		c.3716A>C	p.Gln1239Pro	missense	Exon 25 of 33	NP_001307279.2
	TRPM2	NM_001433516.1		c.3566A>C	p.Gln1189Pro	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>C	p.Gln1189Pro	missense	Exon 24 of 32	ENSP00000381023.1
	TRPM2	ENST00000397932.6	TSL:1	c.3716A>C	p.Gln1239Pro	missense	Exon 25 of 33	ENSP00000381026.2
	TRPM2	ENST00000300482.9	TSL:1	c.3566A>C	p.Gln1189Pro	missense	Exon 25 of 33	ENSP00000300482.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00 AC: 0 AN: 233350 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1452458 Hom.: 0 Cov.: 50 AF XY: 0.00 AC XY: 0 AN XY: 721682

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 43736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108618

Other (OTH) AF: 0.00 AC: 0 AN: 59962

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.32
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.024
Sift	Benign	0.090	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.48		Gain of sheet (P = 0.0073)
MVP		0.33
MPC		0.17
ClinPred		0.019	T
GERP RS		-1.3
Varity_R		0.18
gMVP		0.71
Mutation Taster		=94/6	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: rs9978351; hg19: chr21-45844751;