rs864309688
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_005267.5(GJA8):c.134G>C(p.Trp45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W45R) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
GJA8
NM_005267.5 missense
NM_005267.5 missense
Scores
15
3
Clinical Significance
Conservation
PhyloP100: 8.07
Publications
38 publications found
Genes affected
GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]
GJA8 Gene-Disease associations (from GenCC):
- cataract 1 multiple typesInheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- cataract - microcornea syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset nuclear cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset sutural cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- pulverulent cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- total early-onset cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 19 ACMG points.
PM1
In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005267.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-147908088-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2915341.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: -0.35816 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 1 multiple types, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset sutural cataract, pulverulent cataract, total early-onset cataract.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 1-147908089-G-C is Pathogenic according to our data. Variant chr1-147908089-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005267.5. You can select a different transcript below to see updated ACMG assignments.
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152168
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152168
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74334
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41426
American (AMR)
AF:
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5182
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68040
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
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:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Cataract 1 multiple types (3)
2
-
-
Developmental cataract (2)
1
-
-
GJA8-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 1e-04)
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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