Variant 10-35608196-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153368.3(GJD4):c.683C>G(p.Pro228Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,590,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

GJD4
NM_153368.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.08

Variant links:

Genes affected

GJD4 (HGNC:23296): (gap junction protein delta 4) Connexins, such as GJD4, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

GJD4 links:

ENSG00000273312 (HGNC:):

ENSG00000273312 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0215154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJD4	NM_153368.3 linkuse as main transcript	c.683C>G	p.Pro228Arg	missense_variant	2/2	ENST00000321660.2	NP_699199.2	Q96KN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJD4	ENST00000321660.2 linkuse as main transcript	c.683C>G	p.Pro228Arg	missense_variant	2/2	1	NM_153368.3	ENSP00000315070.1		Q96KN9
ENSG00000273312	ENST00000609313.1 linkuse as main transcript	n.-43G>C		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000127

AC:

AN:

205226

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

113412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000960

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.000126

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000977

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.0000639

AC:

AN:

1438948

Hom.:

Cov.:

AF XY:

0.0000685

AC XY:

AN XY:

715006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000705

Gnomad4 ASJ exome

AF:

0.00101

Gnomad4 EAS exome

AF:

0.0000515

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000389

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000595

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.683C>G (p.P228R) alteration is located in exon 2 (coding exon 2) of the GJD4 gene. This alteration results from a C to G substitution at nucleotide position 683, causing the proline (P) at amino acid position 228 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.69

DANN

Benign

0.58

DEOGEN2

Benign

0.023

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.27

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.69

REVEL

Benign

0.28

Sift

Benign

0.69

Sift4G

Benign

0.46

Polyphen

0.016

Vest4

0.16

MVP

0.32

MPC

0.29

ClinPred

0.012

GERP RS

-3.9

Varity_R

0.027

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over