rs1036938

Positions:

• chr15-78944905-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004390.5(CTSH):​c.77G>C​(p.Cys26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,548,060 control chromosomes in the GnomAD database, including 338,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (24274 hom., cov: 33)
  • Exomes 𝑓: 0.66 (314605 hom.)
• Consequence: CTSH NM_004390.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.730

Genes affected

CTSH (HGNC:2535): (cathepsin H) The protein encoded by this gene is a lysosomal cysteine proteinase important in the overall degradation of lysosomal proteins. It is composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. The encoded protein, which belongs to the peptidase C1 protein family, can act both as an aminopeptidase and as an endopeptidase. Increased expression of this gene has been correlated with malignant progression of prostate tumors. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.2443953E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSH	NM_004390.5	c.77G>C	p.Cys26Ser	missense_variant	1/12	ENST00000220166.10	NP_004381.2
CTSH	NM_001319137.2	c.-999G>C		5_prime_UTR_variant	1/13		NP_001306066.1
CTSH	NM_001411095.1	c.-151G>C		5_prime_UTR_variant	1/12		NP_001398024.1
CTSH	XM_017021951.2	c.-116G>C		5_prime_UTR_variant	1/13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.77G>C	p.Cys26Ser	missense_variant	1/12	1	NM_004390.5	ENSP00000220166	P1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80078 AN: 151958 Hom.: 24268 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.542

GnomAD3 exomes AF: 0.571 AC: 86407 AN: 151258 Hom.: 27467 AF XY: 0.587 AC XY: 47212 AN XY: 80436

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.687

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.659 AC: 920637 AN: 1395982 Hom.: 314605 Cov.: 47 AF XY: 0.660 AC XY: 454742 AN XY: 688524

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.434

Gnomad4 ASJ exome AF: 0.691

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.626

Gnomad4 NFE exome AF: 0.701

Gnomad4 OTH exome AF: 0.621

GnomAD4 genome AF: 0.527 AC: 80106 AN: 152078 Hom.: 24274 Cov.: 33 AF XY: 0.524 AC XY: 38944 AN XY: 74362

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.482

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.614

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.545

Alfa AF: 0.653 Hom.: 10858

Bravo AF: 0.501

TwinsUK AF: 0.703 AC: 2607

ALSPAC AF: 0.695 AC: 2679

ESP6500AA AF: 0.307 AC: 1162

ESP6500EA AF: 0.719 AC: 5510

ExAC AF: 0.471 AC: 25643

Asia WGS AF: 0.377 AC: 1312 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.1
DANN	Benign	0.51
DEOGEN2	Benign	0.053	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.060	T;T
MetaRNN	Benign	0.0000042	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.070
Sift	Benign	0.77	T;.
Sift4G	Benign	0.44	T;T
Vest4		0.028
MutPred		0.15		Gain of disorder (P = 0.0093);.;
MPC		0.17
ClinPred		0.0012	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.34
gMVP		0.42

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: rs1036938; hg19: chr15-79237247; COSMIC: COSV54984032;