rs45619342

chr1-147908782-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005267.5(GJA8):c.827C>T(p.Ser276Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 1-147908782-C-T is Pathogenic according to our data. Variant chr1-147908782-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 427758.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA8	NM_005267.5	c.827C>T	p.Ser276Phe	missense_variant	2/2	ENST00000369235.2
GJA8	XM_011509417.3	c.827C>T	p.Ser276Phe	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA8	ENST00000369235.2	c.827C>T	p.Ser276Phe	missense_variant	2/2		NM_005267.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 1 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

research

Zheng Lab, Zhongnan Hospital of Wuhan University

Feb 01, 2008

S276F (c. 827C>T) mutation in the connexin 50 gene was found in a Chinese five-generation family with the pulverulent nuclear cataract. This mutation was segregated with the phenotype of 10 affected family members who participated in this study. The structure of the lens opacities of the mother of the proband was puffy, and the fibers were tangled under a scanning electron microscope. The fetal nucleus and the embryonal nucleus both displayed white granular opacities. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.19	T
Sift4G	Benign	0.066	T
Polyphen		0.068	B
Vest4		0.73
MutPred		0.89		Gain of sheet (P = 0.0085);
MVP		0.72
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.15
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45619342; hg19: chr1-147380909; COSMIC: COSV53790822;