4-109698309-A-C

Variant names:

• chr4-109698309-A-C
• rs1355329027
• NM_001226.4:c.74T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001226.4(CASP6):​c.74T>G​(p.Phe25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASP6 NM_001226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18744794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP6	NM_001226.4	c.74T>G	p.Phe25Cys	missense_variant	Exon 2 of 7	ENST00000265164.7	NP_001217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP6	ENST00000265164.7	c.74T>G	p.Phe25Cys	missense_variant	Exon 2 of 7	1	NM_001226.4	ENSP00000265164.2
CASP6	ENST00000352981.7	c.41-3609T>G		intron_variant	Intron 1 of 3	1		ENSP00000285333.3
CASP6	ENST00000503684.5	c.20T>G	p.Phe7Cys	missense_variant	Exon 2 of 5	3		ENSP00000427669.1
CASP6	ENST00000505486.2	n.74T>G		non_coding_transcript_exon_variant	Exon 2 of 6			ENSP00000424080.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458588 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33230

American (AMR) AF: 0.00 AC: 0 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111174

Other (OTH) AF: 0.0000166 AC: 1 AN: 60250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74T>G (p.F25C) alteration is located in exon 2 (coding exon 2) of the CASP6 gene. This alteration results from a T to G substitution at nucleotide position 74, causing the phenylalanine (F) at amino acid position 25 to be replaced by a cysteine (C). 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	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;D;D
REVEL	Benign	0.10
Sift	Benign	0.055	T;D;D
Sift4G	Benign	0.23	T;.;D
Polyphen		0.037	B;.;.
Vest4		0.45
MutPred		0.34		Gain of glycosylation at Y26 (P = 0.0037);.;Gain of glycosylation at Y26 (P = 0.0037);
MVP		0.75
MPC		0.26
ClinPred		0.45	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.22
gMVP		0.65
Mutation Taster		=78/22	polymorphism

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

dbSNP: rs1355329027; hg19: chr4-110619465;