Genetic Variant NM_012114.3:c.224G>A (chr19-15053779-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012114.3(CASP14):c.224G>A(p.Arg75Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CASP14
NM_012114.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.77

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13322976).

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.224G>A	p.Arg75Gln	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.224G>A	p.Arg75Gln	missense	Exon 4 of 7	ENSP00000393417.2	P31944
	ENSG00000302149	ENST00000784685.1		n.233-1084C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251050

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111898

Other (OTH)

AF:

0.0000828

AC:

AN:

60394

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

Exome Het

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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.72

M_CAP

Benign

0.0055

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.8

PrimateAI

Benign

0.23

PROVEAN

Benign

0.050

REVEL

Benign

0.13

Sift

Benign

0.30

Sift4G

Benign

0.40

Polyphen

0.21

Vest4

0.35

MVP

0.15

MPC

0.11

ClinPred

0.13

GERP RS

3.9

Varity_R

0.053

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over