rs373749900

Positions:

• chr19-49168682-C-G
• chr19-49168682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000252826.10(TRPM4):​c.742C>G​(p.Arg248Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRPM4 ENST00000252826.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089340955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.742C>G	p.Arg248Gly	missense_variant	6/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.742C>G	p.Arg248Gly	missense_variant	6/25	1	NM_017636.4	ENSP00000252826	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243780 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132334

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459162 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.091	T;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	.;L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.055
Sift	Benign	0.29	.;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0020	.;B;B
Vest4		0.30, 0.29
MutPred		0.56		.;Loss of methylation at R248 (P = 0.0231);Loss of methylation at R248 (P = 0.0231);
MVP		0.49
MPC		0.37
ClinPred		0.096	T
GERP RS		3.4
Varity_R		0.20
gMVP		0.45

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: rs373749900; hg19: chr19-49671939;