chr19-49167957-A-G
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_017636.4(TRPM4):āc.308A>Gā(p.Tyr103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,613,650 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00038 ( 0 hom., cov: 33)
Exomes š: 0.00040 ( 11 hom. )
Consequence
TRPM4
NM_017636.4 missense
NM_017636.4 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 2.76
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 -4 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.752
BP6
Variant 19-49167957-A-G is Benign according to our data. Variant chr19-49167957-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222851.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 58 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.308A>G | p.Tyr103Cys | missense_variant | 4/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.308A>G | p.Tyr103Cys | missense_variant | 4/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000381 AC: 58AN: 152116Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000314 AC: 79AN: 251322Hom.: 1 AF XY: 0.000331 AC XY: 45AN XY: 135838
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GnomAD4 exome AF: 0.000403 AC: 589AN: 1461534Hom.: 11 Cov.: 34 AF XY: 0.000393 AC XY: 286AN XY: 727082
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GnomAD4 genome AF: 0.000381 AC: 58AN: 152116Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31AN XY: 74296
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Progressive familial heart block type IB Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2021 | This variant is associated with the following publications: (PMID: 27527004, 25416190, 26636822, 21887725) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | TRPM4: BS1 - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Aug 09, 2023 | Heterozygous variant NM_017636:c.308A>G (p.Tyr103Cys) in the TRPM4 gene was found on WES data in male proband (39 y.o., Caucasian) with Brugada Syndrome. No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0003573 (Date of access 09-08-2023). This variant has been reported in 2 articles in patients with variable phenotypes (PMID: 26636822; 21887725). Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BS1 - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 29, 2015 | - - |
TRPM4-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 14, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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