rs267606623
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000352.6(ABCC8):c.134C>T(p.Pro45Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P45P) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.134C>T | p.Pro45Leu | missense_variant | 1/39 | ENST00000389817.8 | |
LOC124902641 | XR_007062609.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.134C>T | p.Pro45Leu | missense_variant | 1/39 | 1 | NM_000352.6 | P4 | |
ENST00000662030.1 | n.49G>A | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1459882Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726278
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Diabetes mellitus, permanent neonatal 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2007 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the ABCC8 protein (p.Pro45Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with permanent neonatal diabetes mellitus (PMID: 17668386, 18025408, 25972930). ClinVar contains an entry for this variant (Variation ID: 9110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at