chr19-1491319-T-C

Position:

• chr19-1491319-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138393.4(REEP6):​c.50T>C​(p.Leu17Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: REEP6 NM_138393.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09164497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP6	NM_001329556.3	c.50T>C	p.Leu17Pro	missense_variant	1/6	ENST00000395479.10	NP_001316485.1
REEP6	NM_138393.4	c.50T>C	p.Leu17Pro	missense_variant	1/5	ENST00000233596.8	NP_612402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP6	ENST00000395479.10	c.50T>C	p.Leu17Pro	missense_variant	1/6	3	NM_001329556.3	ENSP00000378861.5
REEP6	ENST00000233596.8	c.50T>C	p.Leu17Pro	missense_variant	1/5	1	NM_138393.4	ENSP00000233596.2
REEP6	ENST00000591735.2	n.154T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1327374 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 653928

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 07, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with REEP6-related conditions. ClinVar contains an entry for this variant (Variation ID: 834265). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 17 of the REEP6 protein (p.Leu17Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.75
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Vest4		0.11
MutPred		0.58		Loss of stability (P = 0.0079);
MVP		0.16
MPC		0.39
ClinPred		0.19	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs2084932592; hg19: chr19-1491318;