19-15053631-G-A

Variant names:

• chr19-15053631-G-A
• rs112231728
• NM_012114.3:c.177G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_012114.3(CASP14):​c.177G>A​(p.Glu59Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00152 in 1,614,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: CASP14 NM_012114.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.94

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 19-15053631-G-A is Benign according to our data. Variant chr19-15053631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713661.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP14	NM_012114.3	c.177G>A	p.Glu59Glu	splice_region_variant, synonymous_variant	Exon 3 of 7	ENST00000427043.4	NP_036246.1
CASP14	XM_011527861.2	c.177G>A	p.Glu59Glu	splice_region_variant, synonymous_variant	Exon 3 of 6		XP_011526163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP14	ENST00000427043.4	c.177G>A	p.Glu59Glu	splice_region_variant, synonymous_variant	Exon 3 of 7	1	NM_012114.3	ENSP00000393417.2

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000955 AC: 240 AN: 251260 AF XY: 0.000876

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00156 AC: 2274 AN: 1461882 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 1093 AN XY: 727242

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33480

Gnomad4 AMR exome AF: 0.000246 AC: 11 AN: 44724

Gnomad4 ASJ exome AF: 0.000842 AC: 22 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86252

Gnomad4 FIN exome AF: 0.0000936 AC: 5 AN: 53420

Gnomad4 NFE exome AF: 0.00195 AC: 2172 AN: 1112006

Gnomad4 Remaining exome AF: 0.000911 AC: 55 AN: 60396

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74450

Gnomad4 AFR AF: 0.000481 AC: 0.000481162 AN: 0.000481162

Gnomad4 AMR AF: 0.000131 AC: 0.000130839 AN: 0.000130839

Gnomad4 ASJ AF: 0.000865 AC: 0.000864553 AN: 0.000864553

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00237 AC: 0.00236702 AN: 0.00236702

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00102

EpiCase AF: 0.00147

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.76
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 8
DS_DL_spliceai		0.20		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs112231728; hg19: chr19-15164442;