1-147907974-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4 BP6_Very_Strong BS1

The NM_005267.5(GJA8):c.19C>A(p.Leu7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.02

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 -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-147907975-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2733979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37018546).
• BP6: Variant 1-147907974-C-A is Benign according to our data. Variant chr1-147907974-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 772629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000762 (116/152272) while in subpopulation AFR AF= 0.00265 (110/41564). AF 95% confidence interval is 0.00224. There are 1 homozygotes in gnomad4. There are 55 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	UniProt
GJA8	NM_005267.5	c.19C>A	p.Leu7Met	missense_variant	2/2	ENST00000369235.2
GJA8	XM_011509417.3	c.19C>A	p.Leu7Met	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA8	ENST00000369235.2	c.19C>A	p.Leu7Met	missense_variant	2/2		NM_005267.5	P1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251418 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135900

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461752 Hom.: 0 Cov.: 35 AF XY: 0.0000715 AC XY: 52 AN XY: 727194

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.000739 AC XY: 55 AN XY: 74444

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000812

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GJA8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cataract 1 multiple types Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MVP		0.91
ClinPred		0.20	T
GERP RS		4.3
Varity_R		0.62
gMVP		0.90

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: rs150441169; hg19: chr1-147380101; COSMIC: COSV53790127;