rs766143193

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000369846.9(LCA5):​c.1676C>T​(p.Ser559Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S559S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LCA5
ENST00000369846.9 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LCA5NM_001122769.3 linkuse as main transcriptc.1676C>T p.Ser559Leu missense_variant 8/8 ENST00000369846.9 NP_001116241.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LCA5ENST00000369846.9 linkuse as main transcriptc.1676C>T p.Ser559Leu missense_variant 8/81 NM_001122769.3 ENSP00000358861 P1
LCA5ENST00000392959.5 linkuse as main transcriptc.1676C>T p.Ser559Leu missense_variant 9/91 ENSP00000376686 P1
ENST00000652956.1 linkuse as main transcriptn.469+5982G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152040
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000320
AC:
8
AN:
249724
Hom.:
0
AF XY:
0.0000519
AC XY:
7
AN XY:
134992
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000230
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1460482
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
726548
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
.;D
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.94
MutPred
0.27
Loss of phosphorylation at S559 (P = 0.0342);Loss of phosphorylation at S559 (P = 0.0342);
MVP
0.88
MPC
0.17
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.82
gMVP
0.59

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.

Other links and lift over

dbSNP: rs766143193; hg19: chr6-80197139; COSMIC: COSV63972165; COSMIC: COSV63972165; API