rs1057519341

Variant names:

• chr19-1496380-CG-C
• rs1057519341
• NM_001329556.3:c.448delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138393.4(REEP6):​c.448delG​(p.Ala150ProfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REEP6 NM_138393.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.56

Genes affected

REEP6 (HGNC:30078): (receptor accessory protein 6) The protein encoded by this gene may be involved in the transport of receptors from the endoplasmic reticulum (ER) to the cell surface. The encoded protein may also play a role in regulating ER membrane structure. This gene is required for the proper development of retinal rods and photoreceptors, with defects in this gene being associated with retinitis pigmentosa 77. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 19-1496380-CG-C is Pathogenic according to our data. Variant chr19-1496380-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 375312.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1496380-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP6	NM_001329556.3	c.448delG	p.Ala150ProfsTer2	frameshift_variant	Exon 4 of 6	ENST00000395479.10	NP_001316485.1
REEP6	NM_138393.4	c.448delG	p.Ala150ProfsTer2	frameshift_variant	Exon 4 of 5	ENST00000233596.8	NP_612402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP6	ENST00000395479.10	c.448delG	p.Ala150ProfsTer2	frameshift_variant	Exon 4 of 6	3	NM_001329556.3	ENSP00000378861.5
REEP6	ENST00000233596.8	c.448delG	p.Ala150ProfsTer2	frameshift_variant	Exon 4 of 5	1	NM_138393.4	ENSP00000233596.2
REEP6	ENST00000395484.4	n.232delG		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000378865.4
REEP6	ENST00000591735.2	n.*200delG		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460904 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726744

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 15, 2023

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.Ala150Profs*2) in the REEP6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in REEP6 are known to be pathogenic (PMID: 27889058, 29120066). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 27889058). ClinVar contains an entry for this variant (Variation ID: 375312). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 77 Pathogenic:1

Jan 26, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519341; hg19: chr19-1496379;