17-68368550-CC-GT

Variant names:

• chr17-68368550-CC-GT
• NM_001267727.2:c.707_708delCCinsGT
• ARSG p.Thr236Ser

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001352903.2(ARSG):​c.705-1_705delCCinsGT​(p.236) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSG NM_001352903.2 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

Genes affected

ARSG (HGNC:24102): (arylsulfatase G) The protein encoded by this gene belongs to the sulfatase enzyme family. Sulfatases hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein displays arylsulfatase activity at acidic pH, as is typical of lysosomal sulfatases, and has been shown to localize in the lysosomes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ARSG Gene-Disease associations (from GenCC):

• Usher syndrome, type 4

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1231746 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of 0 (no position change), new splice context is: tggttctcctgtttcagcAGtag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352903.2. 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
	ARSG	NM_001267727.2	MANE Select	c.707_708delCCinsGT	p.Thr236Ser	missense splice_region	N/A	NP_001254656.1	Q96EG1
	ARSG	NM_001352899.2		c.707_708delCCinsGT	p.Thr236Ser	missense splice_region	N/A	NP_001339828.1	Q96EG1
	ARSG	NM_001352900.2		c.707_708delCCinsGT	p.Thr236Ser	missense splice_region	N/A	NP_001339829.1	Q96EG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSG	ENST00000621439.5	TSL:5 MANE Select	c.707_708delCCinsGT	p.Thr236Ser	missense splice_region	N/A	ENSP00000480910.1	Q96EG1
	ARSG	ENST00000448504.6	TSL:1	c.707_708delCCinsGT	p.Thr236Ser	missense splice_region	N/A	ENSP00000407193.2	Q96EG1
	ARSG	ENST00000452479.6	TSL:5	c.215_216delCCinsGT	p.Thr72Ser	missense splice_region	N/A	ENSP00000413953.2	J9JIG6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-66364691;