17-3636480-A-G

Variant names:

• chr17-3636480-A-G
• rs1031783359
• ENST00000381870.8:c.-458A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001031681.3(CTNS):​c.-458A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 291,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CTNS NM_001031681.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 0 publications found

Genes affected

CTNS (HGNC:2518): (cystinosin, lysosomal cystine transporter) This gene encodes a seven-transmembrane domain protein that functions to transport cystine out of lysosomes. Its activity is driven by the H+ electrochemical gradient of the lysosomal membrane. Mutations in this gene cause cystinosis, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

SHPK (HGNC:1492): (sedoheptulokinase) The protein encoded by this gene has weak homology to several carbohydrate kinases, a class of proteins involved in the phosphorylation of sugars as they enter a cell, inhibiting return across the cell membrane. Sequence variation between this novel gene and known carbohydrate kinases suggests the possibility of a different substrate, cofactor or changes in kinetic properties distinguishing it from other carbohydrate kinases. The gene resides in a region commonly deleted in cystinosis patients, suggesting a role as a modifier for the cystinosis phenotype. The genomic region is also rich in Alu repetitive sequences, frequently involved in chromosomal rearrangements. [provided by RefSeq, Jul 2008]

SHPK Gene-Disease associations (from GenCC):

• isolated sedoheptulokinase deficiency

  Inheritance: AR, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ENSG00000262304 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031681.3. 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
	CTNS	NM_001031681.3		c.-458A>G		5_prime_UTR	Exon 1 of 13	NP_001026851.2	O60931-2
	SHPK	NM_013276.4	MANE Select	c.-261T>C		upstream_gene	N/A	NP_037408.2	Q9UHJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNS	ENST00000381870.8	TSL:1	c.-458A>G		5_prime_UTR	Exon 1 of 13	ENSP00000371294.3	O60931-2
	CTNS	ENST00000673965.1		c.-453A>G		5_prime_UTR	Exon 1 of 12	ENSP00000500995.1	O60931-1
	CTNS	ENST00000901058.1		c.-458A>G		5_prime_UTR	Exon 1 of 12	ENSP00000571117.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 1 AN: 291218 Hom.: 0 Cov.: 3 AF XY: 0.00000660 AC XY: 1 AN XY: 151514

African (AFR) AF: 0.00 AC: 0 AN: 6696

American (AMR) AF: 0.00 AC: 0 AN: 7622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9708

East Asian (EAS) AF: 0.00 AC: 0 AN: 20230

South Asian (SAS) AF: 0.00 AC: 0 AN: 23130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1336

European-Non Finnish (NFE) AF: 0.00000550 AC: 1 AN: 181912

Other (OTH) AF: 0.00 AC: 0 AN: 17784

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.0
DANN	Benign	0.42
PhyloP100		-0.066
PromoterAI		0.086	Neutral

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: rs1031783359; hg19: chr17-3539774;