rs1036938

Variant names:

• chr15-78944905-C-G
• rs1036938
• NM_004390.5:c.77G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004390.5. 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
	CTSH	NM_004390.5	MANE Select	c.77G>C	p.Cys26Ser	missense	Exon 1 of 12	NP_004381.2
	CTSH	NM_001411095.1		c.-151G>C		5_prime_UTR	Exon 1 of 12	NP_001398024.1	E9PKT6
	CTSH	NM_001319137.2		c.-999G>C		5_prime_UTR	Exon 1 of 13	NP_001306066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSH	ENST00000220166.10	TSL:1 MANE Select	c.77G>C	p.Cys26Ser	missense	Exon 1 of 12	ENSP00000220166.6	P09668
	CTSH	ENST00000615999.5	TSL:1	c.77G>C	p.Cys26Ser	missense	Exon 1 of 13	ENSP00000483303.2	A0A087X0D5
	CTSH	ENST00000527715.6	TSL:1	n.125G>C		non_coding_transcript_exon	Exon 1 of 11

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

GnomAD2 exomes AF: 0.571 AC: 86407 AN: 151258 AF XY: 0.587

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 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

African (AFR) AF: 0.252 AC: 7947 AN: 31508

American (AMR) AF: 0.434 AC: 15425 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 17370 AN: 25124

East Asian (EAS) AF: 0.104 AC: 3706 AN: 35616

South Asian (SAS) AF: 0.646 AC: 50997 AN: 78982

European-Finnish (FIN) AF: 0.626 AC: 29902 AN: 47770

Middle Eastern (MID) AF: 0.650 AC: 3698 AN: 5688

European-Non Finnish (NFE) AF: 0.701 AC: 755619 AN: 1077826

Other (OTH) AF: 0.621 AC: 35973 AN: 57918

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

African (AFR) AF: 0.267 AC: 11080 AN: 41496

American (AMR) AF: 0.482 AC: 7367 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2356 AN: 3470

East Asian (EAS) AF: 0.107 AC: 551 AN: 5156

South Asian (SAS) AF: 0.614 AC: 2950 AN: 4808

European-Finnish (FIN) AF: 0.629 AC: 6663 AN: 10598

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 47182 AN: 67936

Other (OTH) AF: 0.545 AC: 1153 AN: 2114

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 v4.9

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
MetaRNN	Benign	0.0000042	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.73
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.070
Sift	Benign	0.77	T
Sift4G	Benign	0.44	T
Vest4		0.028
MutPred		0.15		Gain of disorder (P = 0.0093)
MPC		0.17
ClinPred		0.0012	T
GERP RS		2.2
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.34
gMVP		0.42
Mutation Taster		=100/0	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: rs1036938; hg19: chr15-79237247; COSMIC: COSV54984032;