chr4-109694539-T-A

Variant names:

• chr4-109694539-T-A
• NM_001226.4:c.469A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001226.4(CASP6):​c.469A>T​(p.Ile157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 7.58
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32636124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP6	NM_001226.4	c.469A>T	p.Ile157Leu	missense_variant	Exon 5 of 7	ENST00000265164.7	NP_001217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP6	ENST00000265164.7	c.469A>T	p.Ile157Leu	missense_variant	Exon 5 of 7	1	NM_001226.4	ENSP00000265164.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469A>T (p.I157L) alteration is located in exon 5 (coding exon 5) of the CASP6 gene. This alteration results from a A to T substitution at nucleotide position 469, causing the isoleucine (I) at amino acid position 157 to be replaced by a leucine (L). 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	0.22
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.81
DEOGEN2	Benign	0.071	.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.031
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	.;N;.
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0080	B;B;.
Vest4		0.75
MutPred		0.57		.;Loss of methylation at K154 (P = 0.0599);.;
MVP		0.65
MPC		0.22
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.59
Mutation Taster		=32/68	disease causing

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

Other links and lift over

hg19: chr4-110615695;