1-147908759-C-T

Variant names:

• chr1-147908759-C-T
• rs3766503
• NM_005267.5:c.804C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005267.5(GJA8):​c.804C>T​(p.Leu268Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,614,040 control chromosomes in the GnomAD database, including 1,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (206 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1437 hom.)
• Consequence: GJA8 NM_005267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.442
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-147908759-C-T is Benign according to our data. Variant chr1-147908759-C-T is described in ClinVar as Benign. ClinVar VariationId is 259707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0689 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.804C>T	p.Leu268Leu	synonymous	Exon 2 of 2	NP_005258.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	ENST00000369235.2	TSL:6 MANE Select	c.804C>T	p.Leu268Leu	synonymous	Exon 2 of 2	ENSP00000358238.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7171 AN: 152136 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0403 AC: 10130 AN: 251406 AF XY: 0.0410

Gnomad AFR exome AF: 0.0734

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.0344

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0362

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0418 AC: 61056 AN: 1461786 Hom.: 1437 Cov.: 36 AF XY: 0.0422 AC XY: 30699 AN XY: 727202

African (AFR) AF: 0.0758 AC: 2537 AN: 33474

American (AMR) AF: 0.0165 AC: 738 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 1246 AN: 26136

East Asian (EAS) AF: 0.0450 AC: 1788 AN: 39700

South Asian (SAS) AF: 0.0680 AC: 5864 AN: 86252

European-Finnish (FIN) AF: 0.0377 AC: 2013 AN: 53416

Middle Eastern (MID) AF: 0.0475 AC: 274 AN: 5768

European-Non Finnish (NFE) AF: 0.0395 AC: 43878 AN: 1111930

Other (OTH) AF: 0.0450 AC: 2718 AN: 60386

GnomAD4 genome AF: 0.0472 AC: 7181 AN: 152254 Hom.: 206 Cov.: 32 AF XY: 0.0479 AC XY: 3566 AN XY: 74442

African (AFR) AF: 0.0710 AC: 2950 AN: 41544

American (AMR) AF: 0.0245 AC: 375 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3468

East Asian (EAS) AF: 0.0490 AC: 253 AN: 5164

South Asian (SAS) AF: 0.0663 AC: 320 AN: 4826

European-Finnish (FIN) AF: 0.0382 AC: 405 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2616 AN: 68016

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0422 Hom.: 330

Bravo AF: 0.0453

Asia WGS AF: 0.0950 AC: 329 AN: 3478

EpiCase AF: 0.0354

EpiControl AF: 0.0343

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 1 multiple types (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Zonular Pulverulent Cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.6
DANN	Benign	0.70
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3766503; hg19: chr1-147380886; COSMIC: COSV53788208;