Variant 1-34758055-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005268.4(GJB5):c.725A>T(p.Asp242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GJB5
NM_005268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.267

Variant links:

Genes affected

GJB5 (HGNC:4287): (gap junction protein beta 5) This gene encodes a member of the beta-type (group I) connexin family. The encoded protein is a gap junction protein involved in intercellular communication related to epidermal differentiation and environmental sensing. This gene has been linked to non-small cell lung cancer. [provided by RefSeq, Nov 2012]

GJB5 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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18286619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB5	NM_005268.4 link	c.725A>T	p.Asp242Val	missense_variant	2/2	ENST00000338513.1	NP_005259.1	O95377A0A654IE64
GJB5	XM_005270751.4 link	c.725A>T	p.Asp242Val	missense_variant	2/2		XP_005270808.1	O95377A0A654IE64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB5	ENST00000338513.1 link	c.725A>T	p.Asp242Val	missense_variant	2/2	1	NM_005268.4	ENSP00000340811.1		O95377
SMIM12	ENST00000426886.1 link	n.208-39646T>A		intron_variant		1		ENSP00000429902.1		E5RH51

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151310

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151310

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73852

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

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:

0.00

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

Nov 13, 2024

The c.725A>T (p.D242V) alteration is located in exon 2 (coding exon 1) of the GJB5 gene. This alteration results from a A to T substitution at nucleotide position 725, causing the aspartic acid (D) at amino acid position 242 to be replaced by a valine (V). 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

0.090

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.18

MetaSVM

Uncertain

-0.017

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.51

Sift

Benign

0.090

Sift4G

Benign

0.23

Polyphen

0.11

Vest4

0.31

MutPred

0.34

Loss of disorder (P = 0.0182);

MVP

0.90

MPC

0.24

ClinPred

0.28

GERP RS

5.7

Varity_R

0.12

gMVP

0.34

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