11-104998981-G-A

Variant names:

• chr11-104998981-G-A
• rs523104
• NM_004347.5:c.1000C>T

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801
• Publications: 47 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 -2 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	NM_004347.5	MANE Select	c.1000C>T	p.Leu334Phe	missense	Exon 7 of 10	NP_004338.3
	CASP5	NM_001136112.3		c.1039C>T	p.Leu347Phe	missense	Exon 7 of 10	NP_001129584.1
	CASP5	NM_001136109.3		c.826C>T	p.Leu276Phe	missense	Exon 6 of 9	NP_001129581.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	ENST00000260315.8	TSL:5 MANE Select	c.1000C>T	p.Leu334Phe	missense	Exon 7 of 10	ENSP00000260315.3
	CASP5	ENST00000393141.6	TSL:5	c.1039C>T	p.Leu347Phe	missense	Exon 7 of 10	ENSP00000376849.2
	CASP5	ENST00000526056.5	TSL:5	c.1039C>T	p.Leu347Phe	missense	Exon 7 of 9	ENSP00000436877.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 11911

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.80
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.018
Sift	Benign	0.70	T
Sift4G	Benign	0.70	T
Polyphen		0.0040	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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs523104; hg19: chr11-104869708;