chr19-15053630-A-G

Position:

• chr19-15053630-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012114.3(CASP14):​c.176A>G​(p.Glu59Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP14 NM_012114.3 missense, splice_region
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP14	NM_012114.3	c.176A>G	p.Glu59Gly	missense_variant, splice_region_variant	3/7	ENST00000427043.4	NP_036246.1
CASP14	XM_011527861.2	c.176A>G	p.Glu59Gly	missense_variant, splice_region_variant	3/6		XP_011526163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP14	ENST00000427043.4	c.176A>G	p.Glu59Gly	missense_variant, splice_region_variant	3/7	1	NM_012114.3	ENSP00000393417.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2024

The c.176A>G (p.E59G) alteration is located in exon 3 (coding exon 2) of the CASP14 gene. This alteration results from a A to G substitution at nucleotide position 176, causing the glutamic acid (E) at amino acid position 59 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.097
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.044	D
Polyphen		0.0	B
Vest4		0.36
MutPred		0.54		Gain of catalytic residue at A58 (P = 0.0538);
MVP		0.17
MPC		0.041
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15164441;