chr19-15051947-A-G

Variant names:

• chr19-15051947-A-G
• rs2158468
• NM_012114.3:c.-46-259A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012114.3(CASP14):​c.-46-259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 151,436 control chromosomes in the GnomAD database, including 17,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.47 (17278 hom., cov: 29)
• Consequence: CASP14 NM_012114.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.303
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 19-15051947-A-G is Benign according to our data. Variant chr19-15051947-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

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.-46-259A>G		intron	N/A	NP_036246.1	P31944

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP14	ENST00000427043.4	TSL:1 MANE Select	c.-46-259A>G		intron	N/A	ENSP00000393417.2	P31944
	ENSG00000302149	ENST00000784685.1		n.340+641T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.475 AC: 71845 AN: 151318 Hom.: 17267 Cov.: 29

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.483

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.475 AC: 71890 AN: 151436 Hom.: 17278 Cov.: 29 AF XY: 0.472 AC XY: 34886 AN XY: 73950

African (AFR) AF: 0.561 AC: 23180 AN: 41332

American (AMR) AF: 0.395 AC: 6006 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1705 AN: 3462

East Asian (EAS) AF: 0.402 AC: 2051 AN: 5096

South Asian (SAS) AF: 0.406 AC: 1944 AN: 4790

European-Finnish (FIN) AF: 0.485 AC: 5067 AN: 10440

Middle Eastern (MID) AF: 0.528 AC: 153 AN: 290

European-Non Finnish (NFE) AF: 0.448 AC: 30396 AN: 67806

Other (OTH) AF: 0.480 AC: 1010 AN: 2104

Alfa AF: 0.463 Hom.: 22786

Bravo AF: 0.474

Asia WGS AF: 0.436 AC: 1516 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.25
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2158468; hg19: chr19-15162758;