chr15-78932341-C-T

Variant names:

• chr15-78932341-C-T
• rs2289700
• NM_004390.5:c.492+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.492+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,599,172 control chromosomes in the GnomAD database, including 22,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4383 hom., cov: 32)
  • Exomes 𝑓: 0.12 (18187 hom.)
• Consequence: CTSH NM_004390.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• Publications: 23 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 (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSH	NM_004390.5	c.492+31G>A		intron_variant	Intron 6 of 11	ENST00000220166.10	NP_004381.2
CTSH	NM_001411095.1	c.378+31G>A		intron_variant	Intron 6 of 11		NP_001398024.1
CTSH	NM_001319137.2	c.-446+31G>A		intron_variant	Intron 7 of 12		NP_001306066.1
CTSH	XM_017021951.2	c.438+31G>A		intron_variant	Intron 7 of 12		XP_016877440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSH	ENST00000220166.10	c.492+31G>A		intron_variant	Intron 6 of 11	1	NM_004390.5	ENSP00000220166.6

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29872 AN: 152036 Hom.: 4374 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.0932

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0834

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0966

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.178 AC: 44536 AN: 250006 AF XY: 0.163

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.0967

Gnomad EAS exome AF: 0.646

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0972

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.122 AC: 177211 AN: 1447018 Hom.: 18187 Cov.: 28 AF XY: 0.120 AC XY: 86367 AN XY: 720782

African (AFR) AF: 0.347 AC: 11470 AN: 33036

American (AMR) AF: 0.285 AC: 12704 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0966 AC: 2512 AN: 26016

East Asian (EAS) AF: 0.612 AC: 24238 AN: 39590

South Asian (SAS) AF: 0.0918 AC: 7889 AN: 85956

European-Finnish (FIN) AF: 0.0872 AC: 4649 AN: 53328

Middle Eastern (MID) AF: 0.106 AC: 610 AN: 5740

European-Non Finnish (NFE) AF: 0.0951 AC: 104465 AN: 1098866

Other (OTH) AF: 0.145 AC: 8674 AN: 59906

GnomAD4 genome AF: 0.197 AC: 29905 AN: 152154 Hom.: 4383 Cov.: 32 AF XY: 0.198 AC XY: 14765 AN XY: 74402

African (AFR) AF: 0.341 AC: 14144 AN: 41488

American (AMR) AF: 0.245 AC: 3752 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 323 AN: 3466

East Asian (EAS) AF: 0.628 AC: 3244 AN: 5166

South Asian (SAS) AF: 0.107 AC: 517 AN: 4824

European-Finnish (FIN) AF: 0.0834 AC: 885 AN: 10612

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0966 AC: 6571 AN: 67988

Other (OTH) AF: 0.185 AC: 391 AN: 2114

Alfa AF: 0.135 Hom.: 5737

Bravo AF: 0.220

Asia WGS AF: 0.330 AC: 1149 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2289700; hg19: chr15-79224683; COSMIC: COSV54986518; COSMIC: COSV54986518;