11-104997445-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004347.5(CASP5):c.1144G>C(p.Glu382Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,613,326 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (3 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02381894).
• BP6: Variant 11-104997445-C-G is Benign according to our data. Variant chr11-104997445-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2209080.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP5	NM_004347.5	c.1144G>C	p.Glu382Gln	missense_variant	8/10	ENST00000260315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP5	ENST00000260315.8	c.1144G>C	p.Glu382Gln	missense_variant	8/10	5	NM_004347.5	A2

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000768 AC: 193 AN: 251254 Hom.: 0 AF XY: 0.000862 AC XY: 117 AN XY: 135780

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000988 AC: 1443 AN: 1461034 Hom.: 3 Cov.: 29 AF XY: 0.000988 AC XY: 718 AN XY: 726858

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.040
Dann	Benign	0.56
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.047	T;T;T;T;.;.
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.024	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.082
MVP		0.14
MPC		0.20
ClinPred		0.0017	T
GERP RS		-7.2
Varity_R		0.056
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs45458695; hg19: chr11-104868172;