19-15053748-C-G

Position:

• chr19-15053748-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012114.3(CASP14):​c.193C>G​(p.Leu65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,613,570 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: CASP14 NM_012114.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.38

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 (MetaRNN=0.0058663785).
• BP6: Variant 19-15053748-C-G is Benign according to our data. Variant chr19-15053748-C-G is described in ClinVar as [Benign]. Clinvar id is 781880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000621 (907/1461326) while in subpopulation AMR AF= 0.0191 (853/44712). AF 95% confidence interval is 0.018. There are 7 homozygotes in gnomad4_exome. There are 370 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP14	NM_012114.3	c.193C>G	p.Leu65Val	missense_variant	4/7	ENST00000427043.4	NP_036246.1
CASP14	XM_011527861.2	c.193C>G	p.Leu65Val	missense_variant	4/6		XP_011526163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP14	ENST00000427043.4	c.193C>G	p.Leu65Val	missense_variant	4/7	1	NM_012114.3	ENSP00000393417	P1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00294 AC: 738 AN: 250938 Hom.: 5 AF XY: 0.00213 AC XY: 289 AN XY: 135640

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000621 AC: 907 AN: 1461326 Hom.: 7 Cov.: 32 AF XY: 0.000509 AC XY: 370 AN XY: 726866

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74428

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.00227

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.000577 AC: 2 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.060
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Benign	0.29	T
Polyphen		0.89	P
Vest4		0.53
MVP		0.067
MPC		0.18
ClinPred		0.075	T
GERP RS		-9.8
Varity_R		0.13
gMVP		0.59

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: rs182103308; hg19: chr19-15164559;