rs762428211
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_017636.4(TRPM4):c.2638G>A(p.Gly880Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,580,366 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 (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
TRPM4
NM_017636.4 missense
NM_017636.4 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 0.801
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19562286).
BS2
?
High AC in GnomAd at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.2638G>A | p.Gly880Ser | missense_variant | 17/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.2638G>A | p.Gly880Ser | missense_variant | 17/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152178Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000358 AC: 7AN: 195392Hom.: 0 AF XY: 0.0000556 AC XY: 6AN XY: 107968
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GnomAD4 exome AF: 0.0000238 AC: 34AN: 1428188Hom.: 0 Cov.: 32 AF XY: 0.0000211 AC XY: 15AN XY: 709426
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152178Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Progressive familial heart block type IB Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 880 of the TRPM4 protein (p.Gly880Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. ClinVar contains an entry for this variant (Variation ID: 409637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Progressive familial heart block type IB;C5193144:Erythrokeratodermia variabilis et progressiva 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 08, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2022 | The p.G880S variant (also known as c.2638G>A), located in coding exon 17 of the TRPM4 gene, results from a G to A substitution at nucleotide position 2638. The glycine at codon 880 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of helix (P = 0.2059);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at