6-63806208-T-TA

Variant names:

• chr6-63806208-T-TA
• rs1770904723
• NM_001142800.2:c.7392dupT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001142800.2(EYS):​c.7392dupT​(p.Thr2465TyrfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EYS NM_001142800.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.71

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

SCAT8 (HGNC:40967): (S-phase cancer associated transcript 8)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-63806208-T-TA is Pathogenic according to our data. Variant chr6-63806208-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 867095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.7392dupT	p.Thr2465TyrfsTer12	frameshift_variant	Exon 37 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.7392dupT	p.Thr2465TyrfsTer12	frameshift_variant	Exon 37 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.7392dupT	p.Thr2465TyrfsTer12	frameshift_variant	Exon 37 of 43	5	NM_001142800.2	ENSP00000424243.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399154 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 690072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal dystrophy Pathogenic:2

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 11, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr2465Tyrfs*12) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa ‚Äã (PMID: 32218477). ClinVar contains an entry for this variant (Variation ID: 867095). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 25 Pathogenic:1

Mar 03, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1770904723; hg19: chr6-64516101;