9-87728650-A-C

Position:

• chr9-87728650-A-C

Variant summary

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

The NM_001912.5(CTSL):​c.462A>C​(p.Lys154Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSL NM_001912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

Genes affected

CTSL (HGNC:2537): (cathepsin L) The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Additionally, this protein cleaves the S1 subunit of the SARS-CoV-2 spike protein, which is necessary for entry of the virus into the cell. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSL	NM_001912.5	c.462A>C	p.Lys154Asn	missense_variant	5/8	ENST00000343150.10	NP_001903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSL	ENST00000343150.10	c.462A>C	p.Lys154Asn	missense_variant	5/8	1	NM_001912.5	ENSP00000345344.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Aug 20, 2023

The c.462A>C (p.K154N) alteration is located in exon 5 (coding exon 4) of the CTSL gene. This alteration results from a A to C substitution at nucleotide position 462, causing the lysine (K) at amino acid position 154 to be replaced by an asparagine (N). 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	0.60
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.5	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.85	P;P;.
Vest4		0.35
MutPred		0.68		Loss of ubiquitination at K154 (P = 0.0341);Loss of ubiquitination at K154 (P = 0.0341);Loss of ubiquitination at K154 (P = 0.0341);
MVP		0.92
MPC		0.49
ClinPred		0.99	D
GERP RS		0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.68

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: chr9-90343565;