11-104995788-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_004347.5(CASP5):c.1261C>T(p.Arg421Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,612,250 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: CASP5 NM_004347.5 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.115

Genes affected

CASP5 (HGNC:1506): (caspase 5) 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. Overexpression of the active form of this enzyme induces apoptosis in fibroblasts. Max, a central component of the Myc/Max/Mad transcription regulation network important for cell growth, differentiation, and apoptosis, is cleaved by this protein; this process requires Fas-mediated dephosphorylation of Max. The expression of this gene is regulated by interferon-gamma and lipopolysaccharide. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_004347.5 Downstream stopcodon found after 67 codons.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP5	NM_004347.5	c.1261C>T	p.Arg421Ter	stop_gained	9/10	ENST00000260315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP5	ENST00000260315.8	c.1261C>T	p.Arg421Ter	stop_gained	9/10	5	NM_004347.5	A2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 250424 Hom.: 2 AF XY: 0.00123 AC XY: 166 AN XY: 135300

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000558

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00134 AC: 1951 AN: 1460062 Hom.: 6 Cov.: 29 AF XY: 0.00131 AC XY: 953 AN XY: 726408

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000997

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000569

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74394

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00136 Hom.: 2

Bravo AF: 0.00121

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00114 AC: 138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00192

EpiControl AF: 0.00238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 07, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	33
Dann	Benign	0.87
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.037	N
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
Vest4		0.83
GERP RS		-0.23

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

LitVar

Other links and lift over

dbSNP: rs141361242; hg19: chr11-104866515;