rs769277893

chr19-15055214-GAC-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_012114.3(CASP14):c.462_463del(p.Asp154GlufsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CASP14 NM_012114.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 1.78

Genes affected

CASP14 (HGNC:1502): (caspase 14) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This caspase has been shown to be processed and activated by caspase 8 and caspase 10 in vitro, and by anti-Fas agonist antibody or TNF-related apoptosis inducing ligand in vivo. The expression and processing of this caspase may be involved in keratinocyte terminal differentiation, which is important for the formation of the skin barrier. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-15055214-GAC-G is Benign according to our data. Variant chr19-15055214-GAC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375306.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP14	NM_012114.3	c.462_463del	p.Asp154GlufsTer27	frameshift_variant	5/7	ENST00000427043.4
CASP14	XM_011527861.2	c.462_463del	p.Asp154GlufsTer33	frameshift_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP14	ENST00000427043.4	c.462_463del	p.Asp154GlufsTer27	frameshift_variant	5/7	1	NM_012114.3	P1
CASP14	ENST00000598738.1	n.315_316del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152072 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000482 AC: 121 AN: 251294 Hom.: 0 AF XY: 0.000435 AC XY: 59 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461860 Hom.: 0 AF XY: 0.000171 AC XY: 124 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152190 Hom.: 1 Cov.: 31 AF XY: 0.000524 AC XY: 39 AN XY: 74406

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000710

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ichthyosis, congenital, autosomal recessive 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 24, 2022

Variant summary: CASP14 c.462_463delCA (p.Asp154GlufsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00043 in 150844 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0035 in the gnomAD database (v3.1 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASP14 causing (severe) Lamellar Ichthyosis phenotype (0.00025), suggesting that the variant is likely not associated with a severe, highly penetrant ichthyotic phenotype. On the other hand, the variant, c.462_463delCA, has also been reported in the literature in three homozygous individuals, from two families, who were affected with a mild form of ichthyosis, although phenotype details were provided only for one of these patients, describing whitish scales over body, without erythema or other symptoms (Kirchmeier_2017). These data indicate that the variant might be associated with a milder disease, possibly with incomplete penetrance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other truncations have been reported in affected individuals (HGMD). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for a milder disease phenotype. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769277893; hg19: chr19-15166025;