rs2230061

Variant names:

• chr1-150755063-G-A
• rs2230061
• NM_004079.5:c.337C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-150755063-G-A
• chr1-150755063-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004079.5(CTSS):​c.337C>T​(p.Arg113Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,552 control chromosomes in the GnomAD database, including 109,160 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.34 (9315 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99845 hom.)
• Consequence: CTSS NM_004079.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.701
• Publications: 63 publications found

Genes affected

CTSS (HGNC:2545): (cathepsin S) The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.346767E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.337C>T	p.Arg113Trp	missense_variant	Exon 4 of 8	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.249+2795C>T		intron_variant	Intron 3 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.337C>T	p.Arg113Trp	missense_variant	Exon 4 of 8	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52322 AN: 151878 Hom.: 9308 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.397

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.377 AC: 94801 AN: 251262 AF XY: 0.386

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.335

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.367 AC: 535683 AN: 1461556 Hom.: 99845 Cov.: 37 AF XY: 0.371 AC XY: 270045 AN XY: 727076

African (AFR) AF: 0.281 AC: 9394 AN: 33478

American (AMR) AF: 0.397 AC: 17764 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 11179 AN: 26120

East Asian (EAS) AF: 0.363 AC: 14406 AN: 39678

South Asian (SAS) AF: 0.520 AC: 44846 AN: 86228

European-Finnish (FIN) AF: 0.351 AC: 18719 AN: 53396

Middle Eastern (MID) AF: 0.403 AC: 2324 AN: 5768

European-Non Finnish (NFE) AF: 0.355 AC: 394406 AN: 1111794

Other (OTH) AF: 0.375 AC: 22645 AN: 60382

GnomAD4 genome AF: 0.344 AC: 52345 AN: 151996 Hom.: 9315 Cov.: 32 AF XY: 0.350 AC XY: 25966 AN XY: 74268

African (AFR) AF: 0.274 AC: 11383 AN: 41488

American (AMR) AF: 0.405 AC: 6184 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1501 AN: 3466

East Asian (EAS) AF: 0.355 AC: 1835 AN: 5166

South Asian (SAS) AF: 0.529 AC: 2552 AN: 4822

European-Finnish (FIN) AF: 0.345 AC: 3636 AN: 10552

Middle Eastern (MID) AF: 0.386 AC: 112 AN: 290

European-Non Finnish (NFE) AF: 0.356 AC: 24155 AN: 67924

Other (OTH) AF: 0.352 AC: 745 AN: 2114

Alfa AF: 0.355 Hom.: 26616

Bravo AF: 0.339

TwinsUK AF: 0.353 AC: 1309

ALSPAC AF: 0.364 AC: 1402

ESP6500AA AF: 0.279 AC: 1229

ESP6500EA AF: 0.355 AC: 3052

ExAC AF: 0.376 AC: 45695

Asia WGS AF: 0.382 AC: 1326 AN: 3478

EpiCase AF: 0.359

EpiControl AF: 0.366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.70
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.055
Sift	Benign	0.11	T
Sift4G	Uncertain	0.045	D
Polyphen		0.90	P
Vest4		0.052
MPC		0.81
ClinPred		0.014	T
GERP RS		1.2
Varity_R		0.17
gMVP		0.52
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230061; hg19: chr1-150727539; COSMIC: COSV64566034; COSMIC: COSV64566034;