rs191205969
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001252024.2(TRPM1):āc.362T>Cā(p.Leu121Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00016 ( 0 hom., cov: 32)
Exomes š: 0.00032 ( 0 hom. )
Consequence
TRPM1
NM_001252024.2 missense
NM_001252024.2 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
TRPM1 (HGNC:7146): (transient receptor potential cation channel subfamily M member 1) This gene encodes a member of the transient receptor potential melastatin subfamily of transient receptor potential ion channels. The encoded protein is a calcium permeable cation channel that is expressed in melanocytes and may play a role in melanin synthesis. Specific mutations in this gene are the cause autosomal recessive complete congenital stationary night blindness-1C. The expression of this protein is inversely correlated with melanoma aggressiveness and as such it is used as a prognostic marker for melanoma metastasis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-31068010-A-G is Pathogenic according to our data. Variant chr15-31068010-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6227.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr15-31068010-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-31068010-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-31068010-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRPM1 | NM_001252024.2 | c.362T>C | p.Leu121Pro | missense_variant | 5/28 | ENST00000256552.11 | NP_001238953.1 | |
TRPM1 | NM_001252020.2 | c.413T>C | p.Leu138Pro | missense_variant | 4/27 | NP_001238949.1 | ||
TRPM1 | NM_002420.6 | c.296T>C | p.Leu99Pro | missense_variant | 4/27 | NP_002411.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRPM1 | ENST00000256552.11 | c.362T>C | p.Leu121Pro | missense_variant | 5/28 | 1 | NM_001252024.2 | ENSP00000256552.7 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000120 AC: 30AN: 249556Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135394
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GnomAD4 exome AF: 0.000321 AC: 469AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 234AN XY: 727246
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74430
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 16, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the TRPM1 protein (p.Leu99Pro). This variant is present in population databases (rs191205969, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital stationary night blindness (PMID: 19896109, 19896113, 28559085, 29522070). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6227). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 6227; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30487145, 28559085, 25307992, 19896109, 19896113, 29522070, 26582918, 31589614) - |
Congenital stationary night blindness 1C Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;D;T;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MVP
MPC
1.0
ClinPred
D
GERP RS
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