chr2-73452354-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001378454.1(ALMS1):c.5827C>T(p.Arg1943Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict 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. R1943L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001378454.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.5827C>T | p.Arg1943Cys | missense_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.5830C>T | p.Arg1944Cys | missense_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.5827C>T | p.Arg1943Cys | missense_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000100 AC: 25AN: 248988Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 135070
GnomAD4 exome AF: 0.0000711 AC: 104AN: 1461774Hom.: 0 Cov.: 38 AF XY: 0.0000646 AC XY: 47AN XY: 727186
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74450
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 20, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 17, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1944 of the ALMS1 protein (p.Arg1944Cys). This variant is present in population databases (rs370398704, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 393252). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 393252; Landrum et al., 2016) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2021 | The p.R1944C variant (also known as c.5830C>T), located in coding exon 8 of the ALMS1 gene, results from a C to T substitution at nucleotide position 5830. The arginine at codon 1944 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at