19-15052105-T-A

Position:

• chr19-15052105-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012114.3(CASP14):​c.-46-101T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 732,860 control chromosomes in the GnomAD database, including 7,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1176 hom., cov: 31)
  • Exomes 𝑓: 0.14 (6486 hom.)
• Consequence: CASP14 NM_012114.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0980

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-15052105-T-A is Benign according to our data. Variant chr19-15052105-T-A is described in ClinVar as [Benign]. Clinvar id is 1238465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP14	NM_012114.3	c.-46-101T>A		intron_variant		ENST00000427043.4	NP_036246.1
CASP14	XM_011527861.2	c.-46-101T>A		intron_variant			XP_011526163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP14	ENST00000427043.4	c.-46-101T>A		intron_variant		1	NM_012114.3	ENSP00000393417	P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17494 AN: 151952 Hom.: 1172 Cov.: 31

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.0860

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.0770

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.142 AC: 82200 AN: 580790 Hom.: 6486 AF XY: 0.144 AC XY: 44579 AN XY: 308734

Gnomad4 AFR exome AF: 0.0549

Gnomad4 AMR exome AF: 0.0849

Gnomad4 ASJ exome AF: 0.0463

Gnomad4 EAS exome AF: 0.0978

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.115 AC: 17515 AN: 152070 Hom.: 1176 Cov.: 31 AF XY: 0.118 AC XY: 8737 AN XY: 74340

Gnomad4 AFR AF: 0.0616

Gnomad4 AMR AF: 0.0858

Gnomad4 ASJ AF: 0.0456

Gnomad4 EAS AF: 0.0764

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.100

Alfa AF: 0.136 Hom.: 178

Bravo AF: 0.105

Asia WGS AF: 0.149 AC: 523 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.8
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2239364; hg19: chr19-15162916;