19-1491296-G-C

Position:

chr19-1491296-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_138393.4(REEP6):c.27G>C(p.Glu9Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000055 in 1,472,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

REEP6
NM_138393.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.641

Variant links:

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 links:

REEP6 (HGNC:):

REEP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03444484).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000269 (41/152374) while in subpopulation AFR AF= 0.000938 (39/41592). AF 95% confidence interval is 0.000705. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP6	NM_001329556.3 linkuse as main transcript	c.27G>C	p.Glu9Asp	missense_variant	1/6	ENST00000395479.10	NP_001316485.1
REEP6	NM_138393.4 linkuse as main transcript	c.27G>C	p.Glu9Asp	missense_variant	1/5	ENST00000233596.8	NP_612402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
REEP6	ENST00000395479.10 linkuse as main transcript	c.27G>C	p.Glu9Asp	missense_variant	1/6	3	NM_001329556.3	ENSP00000378861.5	Q96HR9-1
REEP6	ENST00000233596.8 linkuse as main transcript	c.27G>C	p.Glu9Asp	missense_variant	1/5	1	NM_138393.4	ENSP00000233596.2	Q96HR9-2
REEP6	ENST00000591735.2 linkuse as main transcript	n.131G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

77118

Hom.:

AF XY:

0.0000713

AC XY:

AN XY:

42074

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.000286

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1320580

Hom.:

Cov.:

AF XY:

0.0000338

AC XY:

AN XY:

649992

show subpopulations

Gnomad4 AFR exome

AF:

0.000919

Gnomad4 AMR exome

AF:

0.000181

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:

0.00000191

Gnomad4 OTH exome

AF:

0.0000918

GnomAD4 genome

AF:

0.000269

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000497

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000360

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 9 of the REEP6 protein (p.Glu9Asp). This variant is present in population databases (rs146326095, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with REEP6-related conditions. ClinVar contains an entry for this variant (Variation ID: 860974). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2024

The c.27G>C (p.E9D) alteration is located in exon 1 (coding exon 1) of the REEP6 gene. This alteration results from a G to C substitution at nucleotide position 27, causing the glutamic acid (E) at amino acid position 9 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.75

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.56

M_CAP

Benign

0.051

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.99

REVEL

Benign

0.016

Sift

Benign

0.65

Sift4G

Benign

0.70

Vest4

0.092

MutPred

0.32

Loss of loop (P = 0.1242);

MVP

0.23

MPC

0.22

ClinPred

0.012

GERP RS

0.57

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over