19-15053748-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.38

Publications

1 publications found

Variant links:

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

CASP14 links:

ENSG00000302149 (HGNC:):

ENSG00000302149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 370 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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.193C>G	p.Leu65Val	missense	Exon 4 of 7	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.193C>G	p.Leu65Val	missense	Exon 4 of 7	ENSP00000393417.2	P31944
	ENSG00000302149	ENST00000784685.1		n.233-1053G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00294

AC:

738

AN:

250938

AF XY:

0.00213

show subpopulations

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 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.:

Cov.:

AF XY:

0.000509

AC XY:

370

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33470

American (AMR)

AF:

0.0191

AC:

853

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111546

Other (OTH)

AF:

0.000662

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152244

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.0112

AC:

171

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.00227

ExAC

AF:

0.00214

AC:

260

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.060

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

-4.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.13

Sift

Uncertain

0.015

Sift4G

Benign

0.29

Polyphen

0.89

Vest4

0.53

MVP

0.067

MPC

0.18

ClinPred

0.075

GERP RS

-9.8

Varity_R

0.13

gMVP

0.59

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over