rs61755277

Variant names:

• chr19-15053628-C-T
• rs61755277
• NM_012114.3:c.174C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_012114.3(CASP14):​c.174C>T​(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,614,062 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: CASP14 NM_012114.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.305
• Publications: 2 publications found

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

ENSG00000302149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-15053628-C-T is Benign according to our data. Variant chr19-15053628-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 770655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.305 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.174C>T	p.Ala58Ala	synonymous	Exon 3 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.174C>T	p.Ala58Ala	synonymous	Exon 3 of 7	ENSP00000393417.2	P31944
	ENSG00000302149	ENST00000784685.1		n.233-933G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00468

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00234 AC: 587 AN: 251250 AF XY: 0.00239

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00395 AC: 5776 AN: 1461878 Hom.: 18 Cov.: 32 AF XY: 0.00389 AC XY: 2832 AN XY: 727238

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00183 AC: 82 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86252

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00470 AC: 5221 AN: 1112002

Other (OTH) AF: 0.00300 AC: 181 AN: 60396

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74398

African (AFR) AF: 0.000578 AC: 24 AN: 41526

American (AMR) AF: 0.00164 AC: 25 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00468 AC: 318 AN: 68004

Other (OTH) AF: 0.00285 AC: 6 AN: 2102

Alfa AF: 0.00375 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		-0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61755277; hg19: chr19-15164439; COSMIC: COSV55666109; COSMIC: COSV55666109;