1-34761432-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2

The NM_153212.3(GJB4):c.178T>G(p.Cys60Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

GJB4
NM_153212.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 7.97

Variant links:

Genes affected

GJB4 (HGNC:4286): (gap junction protein beta 4) This gene encodes a transmembrane connexin protein that is a component of gap junctions. Mutations in this gene have been associated with erythrokeratodermia variabilis, progressive symmetric erythrokeratoderma and hearing impairment. [provided by RefSeq, Dec 2009]

GJB4 links:

(HGNC:):

links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

BP6

Variant 1-34761432-T-G is Benign according to our data. Variant chr1-34761432-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1608519.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB4	NM_153212.3 linkuse as main transcript	c.178T>G	p.Cys60Gly	missense_variant	2/2	ENST00000339480.3
GJB4	XM_011540679.3 linkuse as main transcript	c.178T>G	p.Cys60Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GJB4	ENST00000339480.3 linkuse as main transcript	c.178T>G	p.Cys60Gly	missense_variant	2/2	2	NM_153212.3	P1
	ENST00000542839.1 linkuse as main transcript	n.554A>C		non_coding_transcript_exon_variant	2/2	5
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-43023A>C		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251114

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.178T>G (p.C60G) alteration is located in exon 2 (coding exon 1) of the GJB4 gene. This alteration results from a T to G substitution at nucleotide position 178, causing the cysteine (C) at amino acid position 60 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

- -

Erythrokeratodermia variabilis et progressiva 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.58

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-12

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.95

MPC

0.52

ClinPred

0.97

GERP RS

5.4

Varity_R

0.98

gMVP

0.94

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