rs142415337

Positions:

• chr1-147908340-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_005267.5(GJA8):​c.385G>A​(p.Val129Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.927

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a disulfide_bond (size 140) in uniprot entity CXA8_HUMAN there are 45 pathogenic changes around while only 5 benign (90%) in NM_005267.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.01220268).
• BP6: Variant 1-147908340-G-A is Benign according to our data. Variant chr1-147908340-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292466.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr1-147908340-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000676 (103/152328) while in subpopulation NFE AF= 0.00112 (76/68018). AF 95% confidence interval is 0.000915. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA8	NM_005267.5	c.385G>A	p.Val129Ile	missense_variant	2/2	ENST00000369235.2	NP_005258.2
GJA8	XM_011509417.3	c.385G>A	p.Val129Ile	missense_variant	1/2		XP_011507719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2	c.385G>A	p.Val129Ile	missense_variant	2/2	6	NM_005267.5	ENSP00000358238.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000816 AC: 205 AN: 251334 Hom.: 0 AF XY: 0.000846 AC XY: 115 AN XY: 135862

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00125 AC: 1833 AN: 1461874 Hom.: 1 Cov.: 35 AF XY: 0.00124 AC XY: 900 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74492

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.000589

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000733 AC: 89

EpiCase AF: 0.00125

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 1 multiple types Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the GJA8 protein (p.Val129Ile). This variant is present in population databases (rs142415337, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with GJA8-related conditions. ClinVar contains an entry for this variant (Variation ID: 292466). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

GJA8: BS1, BS2 -

Zonular Pulverulent Cataract Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.21
DANN	Benign	0.69
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.31
Sift	Benign	0.71	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.031
MVP		0.52
ClinPred		0.0030	T
GERP RS		-5.6
Varity_R		0.023
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs142415337; hg19: chr1-147380467; COSMIC: COSV105014894;