chr6-79493707-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001122769.3(LCA5):​c.764G>A​(p.Arg255Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LCA5
NM_001122769.3 missense

Scores

4
13
2

Clinical Significance

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

Conservation

PhyloP100: 5.54

Publications

2 publications found
Variant links:
Genes affected
LCA5 (HGNC:31923): (lebercilin LCA5) This gene encodes a protein that is thought to be involved in centrosomal or ciliary functions. Mutations in this gene cause Leber congenital amaurosis type V. Alternatively spliced transcript variants are described. [provided by RefSeq, Oct 2009]
LCA5 Gene-Disease associations (from GenCC):
  • LCA5-related retinopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Leber congenital amaurosis 5
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • Leber congenital amaurosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • severe early-childhood-onset retinal dystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a coiled_coil_region (size 194) in uniprot entity LCA5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001122769.3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LCA5NM_001122769.3 linkc.764G>A p.Arg255Gln missense_variant Exon 4 of 8 ENST00000369846.9 NP_001116241.1 Q86VQ0A0A384MDJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LCA5ENST00000369846.9 linkc.764G>A p.Arg255Gln missense_variant Exon 4 of 8 1 NM_001122769.3 ENSP00000358861.4 Q86VQ0
LCA5ENST00000392959.5 linkc.764G>A p.Arg255Gln missense_variant Exon 5 of 9 1 ENSP00000376686.1 Q86VQ0
LCA5ENST00000467898.3 linkc.764G>A p.Arg255Gln missense_variant Exon 4 of 7 5 ENSP00000474463.1 S4R3K6
ENSG00000231533ENST00000652956.1 linkn.469+12267C>T intron_variant Intron 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
250620
AF XY:
0.0000369
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1461304
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
726954
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33474
American (AMR)
AF:
0.000134
AC:
6
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39642
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53374
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111648
Other (OTH)
AF:
0.00
AC:
0
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41426
American (AMR)
AF:
0.000131
AC:
2
AN:
15262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68012
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Feb 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 255 of the LCA5 protein (p.Arg255Gln). This variant is present in population databases (rs727503995, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 24265693). ClinVar contains an entry for this variant (Variation ID: 167256). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Aug 28, 2014
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

LCA5-related disorder Uncertain:1
Aug 01, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The LCA5 c.764G>A variant is predicted to result in the amino acid substitution p.Arg255Gln. This variant has been reported as an additional allele in an individual with Leber congenital amaurosis that could be explained by variants in a different gene (Eisenberger et al. 2013. PubMed ID: 24265693). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Uncertain
0.078
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
D;D;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.89
.;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.74
D;D;D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Uncertain
2.8
M;M;.
PhyloP100
5.5
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.7
D;D;.
REVEL
Uncertain
0.57
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.0080
D;D;T
Polyphen
1.0
D;D;.
Vest4
0.76
MutPred
0.27
Loss of MoRF binding (P = 0.0206);Loss of MoRF binding (P = 0.0206);Loss of MoRF binding (P = 0.0206);
MVP
0.91
MPC
0.18
ClinPred
0.98
D
GERP RS
5.4
Varity_R
0.57
gMVP
0.22
Mutation Taster
=84/16
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs727503995; hg19: chr6-80203424; API