rs1591071686

Variant names:

• chr11-65879876-T-C
• rs1591071686
• NM_001335.4:c.22T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001335.4(CTSW):​c.22T>C​(p.Ser8Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSW NM_001335.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250

Genes affected

CTSW (HGNC:2546): (cathepsin W) The protein encoded by this gene, a member of the peptidase C1 family, is a cysteine proteinase that may have a specific function in the mechanism or regulation of T-cell cytolytic activity. The encoded protein is found associated with the membrane inside the endoplasmic reticulum of natural killer and cytotoxic T-cells. Expression of this gene is up-regulated by interleukin-2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2665031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSW	NM_001335.4	c.22T>C	p.Ser8Pro	missense_variant	Exon 1 of 10	ENST00000307886.8	NP_001326.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSW	ENST00000307886.8	c.22T>C	p.Ser8Pro	missense_variant	Exon 1 of 10	1	NM_001335.4	ENSP00000311300.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22T>C (p.S8P) alteration is located in exon 1 (coding exon 1) of the CTSW gene. This alteration results from a T to C substitution at nucleotide position 22, causing the serine (S) at amino acid position 8 to be replaced by a proline (P). 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	0.097
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.026	D;D;T
Polyphen		0.97	D;D;.
Vest4		0.37
MutPred		0.59		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);.;
MVP		0.67
MPC		0.40
ClinPred		0.55	D
GERP RS		1.9
Varity_R		0.37
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs1591071686; hg19: chr11-65647347;