rs780430969

Variant names:

• chr11-105003320-C-A
• rs780430969
• NM_004347.5:c.497G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004347.5(CASP5):​c.497G>T​(p.Cys166Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,455,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.497G>T	p.Cys166Phe	missense	Exon 4 of 10	NP_004338.3	P51878-1
	CASP5	NM_001136112.3		c.536G>T	p.Cys179Phe	missense	Exon 4 of 10	NP_001129584.1	P51878-5
	CASP5	NM_001136109.3		c.323G>T	p.Cys108Phe	missense	Exon 3 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.497G>T	p.Cys166Phe	missense	Exon 4 of 10	ENSP00000260315.3	P51878-1
	CASP5	ENST00000393141.6	TSL:5	c.536G>T	p.Cys179Phe	missense	Exon 4 of 10	ENSP00000376849.2	P51878-5
	CASP5	ENST00000526056.5	TSL:5	c.536G>T	p.Cys179Phe	missense	Exon 4 of 9	ENSP00000436877.1	P51878-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000286 AC: 7 AN: 244922 AF XY: 0.0000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000913

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1455360 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 724004

African (AFR) AF: 0.00 AC: 0 AN: 32978

American (AMR) AF: 0.000137 AC: 6 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109340

Other (OTH) AF: 0.00 AC: 0 AN: 60160

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000763 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.66		Gain of loop (P = 0.069)
MVP		0.66
MPC		0.97
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.80
gMVP		0.53
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs780430969; hg19: chr11-104874047;