chr12-52488087-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_005554.4(KRT6A):c.1441G>A(p.Val481Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005554.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT6A | NM_005554.4 | c.1441G>A | p.Val481Ile | missense_variant | 8/9 | ENST00000330722.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT6A | ENST00000330722.7 | c.1441G>A | p.Val481Ile | missense_variant | 8/9 | 1 | NM_005554.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251296Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135808
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461696Hom.: 0 Cov.: 35 AF XY: 0.0000399 AC XY: 29AN XY: 727158
GnomAD4 genome ? AF: 0.000276 AC: 42AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74344
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2023 | The c.1441G>A (p.V481I) alteration is located in exon 8 (coding exon 8) of the KRT6A gene. This alteration results from a G to A substitution at nucleotide position 1441, causing the valine (V) at amino acid position 481 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 481 of the KRT6A protein (p.Val481Ile). This variant is present in population databases (rs201376827, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KRT6A-related conditions. 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 not expected to disrupt KRT6A protein function with a negative predictive value of 80%. 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