1-34757601-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_005268.4(GJB5):​c.271G>A​(p.Val91Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,461,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

GJB5
NM_005268.4 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.10

Publications

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJB5NM_005268.4 linkc.271G>A p.Val91Met missense_variant Exon 2 of 2 ENST00000338513.1 NP_005259.1 O95377A0A654IE64
GJB5XM_005270751.4 linkc.271G>A p.Val91Met missense_variant Exon 2 of 2 XP_005270808.1 O95377A0A654IE64

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB5ENST00000338513.1 linkc.271G>A p.Val91Met missense_variant Exon 2 of 2 1 NM_005268.4 ENSP00000340811.1 O95377
SMIM12ENST00000426886.1 linkn.208-39192C>T intron_variant Intron 2 of 4 1 ENSP00000429902.1 E5RH51

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000676
AC:
17
AN:
251466
AF XY:
0.0000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461870
Hom.:
1
Cov.:
32
AF XY:
0.0000413
AC XY:
30
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.000359
AC:
31
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.271G>A (p.V91M) alteration is located in exon 2 (coding exon 1) of the GJB5 gene. This alteration results from a G to A substitution at nucleotide position 271, causing the valine (V) at amino acid position 91 to be replaced by a methionine (M). 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
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H
PhyloP100
8.1
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.0
D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.76
MutPred
0.70
Gain of helix (P = 0.132);
MVP
0.93
MPC
0.59
ClinPred
0.95
D
GERP RS
5.9
Varity_R
0.59
gMVP
0.84
Mutation Taster
=27/73
disease causing

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

Other links and lift over

dbSNP: rs746577972; hg19: chr1-35223202; API