2-214945020-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_173076.3(ABCA12):βc.7323delCβ(p.Val2442SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_173076.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250884Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135594
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461402Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726988
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74238
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This sequence change creates a premature translational stop signal (p.Val2442Serfs*22) in the ABCA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA12 are known to be pathogenic (PMID: 20672373). ClinVar contains an entry for this variant (Variation ID: 2859). This variant is also known as 7541delC. This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 15756637, 31168818). This variant is present in population databases (rs387906284, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. -
The c.7323delC pathogenic variant in the ABCA12 gene, reported as c.7541delC, has been observed previously in the homozygous state in patients with harlequin ichthyosis (HI) (Kelsell et al., 2005). The deletion causes a frameshift starting with codon Valine 2442, changes this amino acid to a Serine residue and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Val2442SerfsX22. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
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Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A Pathogenic:1
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Autosomal recessive congenital ichthyosis 4B Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at