19-49168695-G-C

Variant names:

• chr19-49168695-G-C
• NM_017636.4:c.755G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017636.4(TRPM4):​c.755G>C​(p.Arg252Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.417

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35995483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.755G>C	p.Arg252Pro	missense_variant	Exon 6 of 25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.755G>C	p.Arg252Pro	missense_variant	Exon 6 of 25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456414 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724162

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.755G>C(p.Arg252Pro) variant in TRPM4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg252Pro variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position in TRPM4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 252 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;D;.
Eigen	Benign	0.0053
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.86	D;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.3	.;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.012	.;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.96, 0.95	.;D;P
Vest4		0.67, 0.67
MutPred		0.54		.;Loss of methylation at R252 (P = 0.0486);Loss of methylation at R252 (P = 0.0486);
MVP		0.84
MPC		0.84
ClinPred		0.92	D
GERP RS		2.4
Varity_R		0.79
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49671952;