chr1-147903581-G-T

Variant names:

• chr1-147903581-G-T
• rs1495960
• NM_005267.5:c.-12+720G>T

Variant summary

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

The NM_005267.5(GJA8):​c.-12+720G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 152,000 control chromosomes in the GnomAD database, including 23,596 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 0.55 (23596 hom., cov: 32)
• Consequence: GJA8 NM_005267.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

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.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	NM_005267.5	MANE Select	c.-12+720G>T		intron	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.-12+720G>T		intron	N/A	ENSP00000358238.1	P48165

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83054 AN: 151882 Hom.: 23535 Cov.: 32

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.547 AC: 83178 AN: 152000 Hom.: 23596 Cov.: 32 AF XY: 0.545 AC XY: 40503 AN XY: 74294

African (AFR) AF: 0.696 AC: 28841 AN: 41454

American (AMR) AF: 0.548 AC: 8369 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3466

East Asian (EAS) AF: 0.515 AC: 2657 AN: 5156

South Asian (SAS) AF: 0.506 AC: 2438 AN: 4820

European-Finnish (FIN) AF: 0.436 AC: 4605 AN: 10560

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.486 AC: 33040 AN: 67956

Other (OTH) AF: 0.539 AC: 1134 AN: 2104

Alfa AF: 0.517 Hom.: 6588

Bravo AF: 0.559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.043
PhyloP100		-2.3

Splicing

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

Other links and lift over

dbSNP: rs1495960; hg19: chr1-147375707;