rs523104

Positions:

• chr11-104998981-G-A
• chr11-104998981-G-C
• chr11-104998981-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004347.5(CASP5):​c.1000C>T​(p.Leu334Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. L334V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0647001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP5	NM_004347.5	c.1000C>T	p.Leu334Phe	missense_variant	7/10	ENST00000260315.8	NP_004338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP5	ENST00000260315.8	c.1000C>T	p.Leu334Phe	missense_variant	7/10	5	NM_004347.5	ENSP00000260315	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.3
DANN	Benign	0.21
DEOGEN2	Benign	0.0081	.;.;T;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.22	T;T;T;T;.;.
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.065	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.42	N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.70	T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T
Polyphen		0.0040	B;B;B;B;B;B
Vest4		0.016
MutPred		0.37		.;.;Loss of disorder (P = 0.1283);.;.;.;
MVP		0.10
MPC		0.21
ClinPred		0.038	T
GERP RS		-4.7
Varity_R		0.032
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs523104; hg19: chr11-104869708;