GJA8

protein-coding

gap junction protein alpha 8, the group of Gap junction proteins

Gene summary

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]

Previous symbols:

CAE1
CZP1
CAE

MANE transcript

NM_005267.5

Inheritance

AD, AR

ClinVar variants

P:86U:172B:51

Top phenotype

Cataract 1, multiple types

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr1:147,902,795-147,909,269

External References & Databases

Ensembl (ENSG00000121634)

Transcript & Mutation Effects

hg38 • Region Span ~6.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract 1 multiple typesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007285

Submitter: G2P

cataract - microcornea syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015300

Submitter: Orphanet

early-onset sutural cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020372

Submitter: Orphanet

cataract 1 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007285

Submitter: Labcorp Genetics (formerly Invitae)

cataract 1 multiple typesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0007285

Submitter: Ambry Genetics

cataract 1 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007285

Submitter: PanelApp Australia

total early-onset cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021548

Submitter: Orphanet

pulverulent cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011430

Submitter: Orphanet

early-onset nuclear cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020376

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cataract 1, multiple typesAD/AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 14059288; 9497259; 10480374; 11846744; 14627691; 16604058; 18006672; 19756179; 21720542; 20019893; 20597646; 20806042; 21921990

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GJA8 variants in ClinVar

13 Conditions Cataloged

Cataract 1 multiple typesTotal: 192

Inborn genetic diseasesTotal: 76

not providedTotal: 63

GJA8-related disorderTotal: 37

GJA8-related disordersTotal: 11

Developmental cataractTotal: 10

not specifiedTotal: 4

Chromosome 1q21.1 deletion syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005267.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	31 clinvar	1 clinvar	35
missense	14 clinvar	63 clinvar	159 clinvar	17 clinvar	2 clinvar	255
nonsense			5 clinvar			5
start loss			1 clinvar			1
frameshift		9 clinvar	4 clinvar			13
splice donor/acceptor (+/-2bp)						0
Total	14	72	172	48	3	309

Highest pathogenic variant AF is 0.000006571684

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005267.5	RefSeq	NP_005258.2	1	MANE Select
ENST00000369235.2	Ensembl	ENSP00000358238.1	1	MANE Select
XM_011509417.3	RefSeq	XP_011507719.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Calcium Regulation in the Cardiac Cell

Biological Process

lens development in camera-type eye
cell-cell signaling
visual perception
protein homooligomerization
transmembrane transport

Molecular Function

gap junction channel activity
channel activity

Cellular Component

integral component of plasma membrane
connexin complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240986
Coding exons: 1
Length: 6448
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125748
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.199	270	261	1.03	0.0000178	2807
Missense (PolyPhen)		58	85.717	0.67665		971
Synonymous	-1.57	145	123	1.18	0.00000959	906
Loss of Function	1.58	6	11.9	0.506	5.16e-7	150

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00093	0.00092	rare
European (Non-Finnish)	0.00015	0.00014	rare
South Asian	0.000066	0.000065	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.;

Recessive Scores

pRec: 0.241

Intolerance Scores

LoFtool: 0.138
RVIS EVS: -0.18
RVIS percentile EVS: 40.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.651

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium