XM_011509417.3:c.1280+196A>G

Variant names:

• chr1-147909431-A-G
• rs2132397
• XM_011509417.3:c.1280+196A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_011509417.3(GJA8):​c.1280+196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,086 control chromosomes in the GnomAD database, including 6,293 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (6293 hom., cov: 32)
• Consequence: GJA8 XM_011509417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.49
• Publications: 5 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 types

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369235.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	NM_005267.5	MANE Select	c.*174A>G		downstream_gene	N/A	NP_005258.2	P48165

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	ENST00000369235.2	TSL:6 MANE Select	c.*174A>G		downstream_gene	N/A	ENSP00000358238.1	P48165

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25094 AN: 151968 Hom.: 6250 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0581

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.110

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.166 AC: 25194 AN: 152086 Hom.: 6293 Cov.: 32 AF XY: 0.163 AC XY: 12149 AN XY: 74360

African (AFR) AF: 0.538 AC: 22292 AN: 41402

American (AMR) AF: 0.0579 AC: 885 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.165 AC: 851 AN: 5158

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4822

European-Finnish (FIN) AF: 0.0440 AC: 467 AN: 10616

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68010

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.0598 Hom.: 2870

Bravo AF: 0.185

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0020
PhyloP100		-2.5

Splicing

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

Other links and lift over

dbSNP: rs2132397; hg19: chr1-147381558;