4-109697680-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001226.4(CASP6):c.172C>T(p.His58Tyr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP6 NM_001226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

CASP6 (HGNC:1507): (caspase 6) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. 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 acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2540356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP6	NM_001226.4	c.172C>T	p.His58Tyr	missense_variant	3/7	ENST00000265164.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP6	ENST00000265164.7	c.172C>T	p.His58Tyr	missense_variant	3/7	1	NM_001226.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.172C>T (p.H58Y) alteration is located in exon 3 (coding exon 3) of the CASP6 gene. This alteration results from a C to T substitution at nucleotide position 172, causing the histidine (H) at amino acid position 58 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	0.0014
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N;D;D
REVEL	Benign	0.15
Sift	Benign	0.052	T;T;D
Sift4G	Uncertain	0.031	D;.;T
Polyphen		0.46	P;.;.
Vest4		0.15
MutPred		0.45		Loss of glycosylation at P62 (P = 0.0507);.;Loss of glycosylation at P62 (P = 0.0507);
MVP		0.84
MPC		0.20
ClinPred		0.61	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-110618836; COSMIC: COSV99488598; COSMIC: COSV99488598;