11-105002146-T-C

Variant names:

• chr11-105002146-T-C
• rs188726405
• NM_004347.5:c.599A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004347.5(CASP5):​c.599A>G​(p.Asn200Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP5	NM_004347.5	c.599A>G	p.Asn200Ser	missense_variant	Exon 5 of 10	ENST00000260315.8	NP_004338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP5	ENST00000260315.8	c.599A>G	p.Asn200Ser	missense_variant	Exon 5 of 10	5	NM_004347.5	ENSP00000260315.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D;D;.;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.6	.;.;H;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;T;T;D;T;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.84
MutPred		0.90		.;.;Gain of catalytic residue at N200 (P = 0.0961);.;.;.;
MVP		0.46
MPC		0.67
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.68
gMVP		0.80

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: rs188726405; hg19: chr11-104872873;