19-49182789-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017636.4(TRPM4):​c.1475A>C​(p.Lys492Thr) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K492R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TRPM4
NM_017636.4 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.20

Publications

0 publications found
Variant links:
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]
TRPM4 Gene-Disease associations (from GenCC):
  • erythrokeratodermia variabilis et progressiva 6
    Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • progressive familial heart block type IB
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • erythrokeratodermia variabilis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • progressive familial heart block
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Brugada syndrome
    Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

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ACMG classification

Classification was made for transcript

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=0.12008059).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRPM4NM_017636.4 linkc.1475A>C p.Lys492Thr missense_variant Exon 11 of 25 ENST00000252826.10 NP_060106.2 Q8TD43-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRPM4ENST00000252826.10 linkc.1475A>C p.Lys492Thr missense_variant Exon 11 of 25 1 NM_017636.4 ENSP00000252826.4 Q8TD43-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
10
DANN
Benign
0.23
DEOGEN2
Benign
0.11
T;.
Eigen
Benign
-0.99
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.075
N
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.4
M;M
PhyloP100
1.2
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.56
N;N
REVEL
Benign
0.018
Sift
Benign
0.61
T;T
Sift4G
Benign
0.55
T;T
Polyphen
0.0060
B;B
Vest4
0.35
MutPred
0.40
Loss of ubiquitination at K492 (P = 0.0071);Loss of ubiquitination at K492 (P = 0.0071);
MVP
0.56
MPC
0.34
ClinPred
0.14
T
GERP RS
1.1
Varity_R
0.065
gMVP
0.31
Mutation Taster
=78/22
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

Publications

Other links and lift over

dbSNP: rs1236428733; hg19: chr19-49686046; API