rs1057519427

Variant names:

• chr19-1496626-A-AC
• rs1057519427
• NM_001329556.3:c.557dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001329556.3(REEP6):​c.557dupC​(p.Val187GlyfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P186P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: REEP6 NM_001329556.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.795
• Publications: 1 publications found

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]

REEP6 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• retinitis pigmentosa 77

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.123 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1496626-A-AC is Pathogenic according to our data. Variant chr19-1496626-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 374991.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329556.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP6	NM_001329556.3	MANE Plus Clinical	c.557dupC	p.Val187GlyfsTer13	frameshift	Exon 5 of 6	NP_001316485.1
	REEP6	NM_138393.4	MANE Select	c.517+177dupC		intron	N/A	NP_612402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP6	ENST00000395479.10	TSL:3 MANE Plus Clinical	c.557dupC	p.Val187GlyfsTer13	frameshift	Exon 5 of 6	ENSP00000378861.5
	REEP6	ENST00000233596.8	TSL:1 MANE Select	c.517+177dupC		intron	N/A	ENSP00000233596.2
	REEP6	ENST00000395484.4	TSL:5	n.341dupC		non_coding_transcript_exon	Exon 3 of 5	ENSP00000378865.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 10

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 77 Pathogenic:1

Jan 19, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=37/63	disease causing (ClinVar)

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: rs1057519427; hg19: chr19-1496625;