rs768777861

Variant names:

• chr9-87728650-A-C
• rs768777861
• NM_001912.5:c.462A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-87728650-A-C
• chr9-87728650-A-G
• chr9-87728650-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ENSG00000304058 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001912.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSL	NM_001912.5	MANE Select	c.462A>C	p.Lys154Asn	missense	Exon 5 of 8	NP_001903.1	P07711-1
	CTSL	NM_001257971.2		c.462A>C	p.Lys154Asn	missense	Exon 5 of 8	NP_001244900.1	P07711-1
	CTSL	NM_001257972.2		c.462A>C	p.Lys154Asn	missense	Exon 5 of 8	NP_001244901.1	P07711-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSL	ENST00000343150.10	TSL:1 MANE Select	c.462A>C	p.Lys154Asn	missense	Exon 5 of 8	ENSP00000345344.5	P07711-1
	CTSL	ENST00000340342.11	TSL:1	c.462A>C	p.Lys154Asn	missense	Exon 6 of 9	ENSP00000365061.5	P07711-1
	CTSL	ENST00000495822.2	TSL:1	n.759A>C		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.021	D
Polyphen		0.85	P
Vest4		0.35
MutPred		0.68		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
Mutation Taster		=46/54	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

dbSNP: rs768777861; hg19: chr9-90343565;