rs2289702

Variant names:

• chr15-78944951-C-T
• rs2289702
• NM_004390.5:c.31G>A

Variant summary

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

The NM_004390.5(CTSH):​c.31G>A​(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 1,546,582 control chromosomes in the GnomAD database, including 8,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 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. G11V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.079 (571 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7583 hom.)
• Consequence: CTSH NM_004390.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.263
• Publications: 46 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=0.001609087).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.31G>A	p.Gly11Arg	missense_variant	Exon 1 of 12	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.-197G>A		5_prime_UTR_variant	Exon 1 of 12		NP_001398024.1
CTSH	NM_001319137.2	c.-1045G>A		5_prime_UTR_variant	Exon 1 of 13		NP_001306066.1
CTSH	XM_017021951.2	c.-162G>A		5_prime_UTR_variant	Exon 1 of 13		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.31G>A	p.Gly11Arg	missense_variant	Exon 1 of 12	1	NM_004390.5	ENSP00000220166.6

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12054 AN: 152090 Hom.: 570 Cov.: 33

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0642

Gnomad ASJ AF: 0.0923

Gnomad EAS AF: 0.0628

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0885

GnomAD2 exomes AF: 0.0927 AC: 13639 AN: 147102 AF XY: 0.0965

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.0655

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0994

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.101 AC: 140898 AN: 1394374 Hom.: 7583 Cov.: 53 AF XY: 0.103 AC XY: 70562 AN XY: 687802

African (AFR) AF: 0.0245 AC: 769 AN: 31380

American (AMR) AF: 0.0604 AC: 2144 AN: 35492

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2341 AN: 25106

East Asian (EAS) AF: 0.0638 AC: 2266 AN: 35526

South Asian (SAS) AF: 0.129 AC: 10206 AN: 78874

European-Finnish (FIN) AF: 0.123 AC: 5795 AN: 46966

Middle Eastern (MID) AF: 0.0738 AC: 415 AN: 5626

European-Non Finnish (NFE) AF: 0.103 AC: 111132 AN: 1077540

Other (OTH) AF: 0.101 AC: 5830 AN: 57864

GnomAD4 genome AF: 0.0792 AC: 12054 AN: 152208 Hom.: 571 Cov.: 33 AF XY: 0.0798 AC XY: 5939 AN XY: 74406

African (AFR) AF: 0.0287 AC: 1193 AN: 41570

American (AMR) AF: 0.0642 AC: 982 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0923 AC: 320 AN: 3468

East Asian (EAS) AF: 0.0626 AC: 323 AN: 5162

South Asian (SAS) AF: 0.135 AC: 648 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1227 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7098 AN: 67972

Other (OTH) AF: 0.0881 AC: 186 AN: 2112

Alfa AF: 0.0961 Hom.: 226

Bravo AF: 0.0713

TwinsUK AF: 0.104 AC: 386

ALSPAC AF: 0.109 AC: 420

ESP6500AA AF: 0.0275 AC: 103

ESP6500EA AF: 0.0889 AC: 663

ExAC AF: 0.0630 AC: 3759

Asia WGS AF: 0.107 AC: 374 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.84
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.80	T
PhyloP100		-0.26
Sift4G	Benign	0.26	T
Vest4		0.030
ClinPred		0.036	T
GERP RS		3.1
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.32
Mutation Taster		=93/7	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: rs2289702; hg19: chr15-79237293; COSMIC: COSV54985858;