chr11-104995788-G-A

Variant names:

• chr11-104995788-G-A
• rs141361242
• NM_004347.5:c.1261C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004347.5(CASP5):​c.1261C>T​(p.Arg421*) 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
• Publications: 10 publications found

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]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004347.5. 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
	CASP5	NM_004347.5	MANE Select	c.1261C>T	p.Arg421*	stop_gained	Exon 9 of 10	NP_004338.3	P51878-1
	CASP5	NM_001136112.3		c.1300C>T	p.Arg434*	stop_gained	Exon 9 of 10	NP_001129584.1	P51878-5
	CASP5	NM_001136109.3		c.1087C>T	p.Arg363*	stop_gained	Exon 8 of 9	NP_001129581.1	P51878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	ENST00000260315.8	TSL:5 MANE Select	c.1261C>T	p.Arg421*	stop_gained	Exon 9 of 10	ENSP00000260315.3	P51878-1
	CASP5	ENST00000393141.6	TSL:5	c.1300C>T	p.Arg434*	stop_gained	Exon 9 of 10	ENSP00000376849.2	P51878-5
	CASP5	ENST00000526056.5	TSL:5	c.1300C>T	p.Arg434*	stop_gained	Exon 9 of 9	ENSP00000436877.1	P51878-5

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

GnomAD2 exomes AF: 0.00113 AC: 284 AN: 250424 AF XY: 0.00123

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 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

African (AFR) AF: 0.000389 AC: 13 AN: 33436

American (AMR) AF: 0.00199 AC: 89 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 26 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000569 AC: 49 AN: 86070

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53394

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5758

European-Non Finnish (NFE) AF: 0.00144 AC: 1598 AN: 1110728

Other (OTH) AF: 0.00172 AC: 104 AN: 60314

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

African (AFR) AF: 0.000409 AC: 17 AN: 41518

American (AMR) AF: 0.00183 AC: 28 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00135 Hom.: 3

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.12
Vest4		0.83
GERP RS		-0.23
Mutation Taster		=197/3	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: rs141361242; hg19: chr11-104866515;