4-109690870-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001226.4(CASP6):c.623T>C(p.Met208Thr) 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 pathogenic 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: 8.92

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP6	NM_001226.4	c.623T>C	p.Met208Thr	missense_variant	6/7	ENST00000265164.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP6	ENST00000265164.7	c.623T>C	p.Met208Thr	missense_variant	6/7	1	NM_001226.4	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.623T>C (p.M208T) alteration is located in exon 6 (coding exon 6) of the CASP6 gene. This alteration results from a T to C substitution at nucleotide position 623, causing the methionine (M) at amino acid position 208 to be replaced by a threonine (T). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.13	T;D
Polyphen		0.38	B;B
Vest4		0.93
MutPred		0.61		.;Loss of stability (P = 0.1822);
MVP		0.91
MPC		0.61
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-110612026;