rs769277893

Variant names:

• chr19-15055214-GAC-G
• rs769277893
• NM_012114.3:c.462_463delCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_012114.3(CASP14):​c.462_463delCA​(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
• Publications: 0 publications found

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]

CASP14 Gene-Disease associations (from GenCC):

• ichthyosis, congenital, autosomal recessive 12

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ENSG00000302149 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• 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 VariationId is 375306.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012114.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP14	NM_012114.3	MANE Select	c.462_463delCA	p.Asp154GlufsTer27	frameshift	Exon 5 of 7	NP_036246.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP14	ENST00000427043.4	TSL:1 MANE Select	c.462_463delCA	p.Asp154GlufsTer27	frameshift	Exon 5 of 7	ENSP00000393417.2
	CASP14	ENST00000598738.1	TSL:2	n.315_316delCA		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000302149	ENST00000784685.1		n.233-2521_233-2520delGT		intron	N/A

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

GnomAD2 exomes AF: 0.000482 AC: 121 AN: 251294 AF XY: 0.000435

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00266 AC: 119 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111992

Other (OTH) AF: 0.000497 AC: 30 AN: 60394

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41536

American (AMR) AF: 0.00353 AC: 54 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000710

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Ichthyosis, congenital, autosomal recessive 12 (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=27/173	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs769277893; hg19: chr19-15166025;