NM_000166.6:c.-6G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000166.6(GJB1):​c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,208,773 control chromosomes in the GnomAD database, including 3 homozygotes. There are 173 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 15 hem., cov: 23)
Exomes 𝑓: 0.00042 ( 3 hom. 158 hem. )

Consequence

GJB1
NM_000166.6 5_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.62

Publications

3 publications found
Variant links:
Genes affected
GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]
GJB1 Gene-Disease associations (from GenCC):
  • Charcot-Marie-Tooth disease X-linked dominant 1
    Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
  • X-linked progressive cerebellar ataxia
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00044 (49/111404) while in subpopulation NFE AF = 0.000887 (47/52996). AF 95% confidence interval is 0.000685. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
BS2
High Hemizygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJB1NM_000166.6 linkc.-6G>A 5_prime_UTR_variant Exon 2 of 2 ENST00000361726.7 NP_000157.1 P08034A0A654ICJ7
GJB1NM_001097642.3 linkc.-6G>A 5_prime_UTR_variant Exon 2 of 2 NP_001091111.1 P08034A0A654ICJ7
GJB1NM_001440770.1 linkc.-6G>A 5_prime_UTR_variant Exon 3 of 3 NP_001427699.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB1ENST00000361726.7 linkc.-6G>A 5_prime_UTR_variant Exon 2 of 2 1 NM_000166.6 ENSP00000354900.6 P08034

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
49
AN:
111349
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000957
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:
0.000887
Gnomad OTH
AF:
0.000661
GnomAD2 exomes
AF:
0.000480
AC:
87
AN:
181315
AF XY:
0.000450
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000730
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000525
Gnomad NFE exome
AF:
0.000906
Gnomad OTH exome
AF:
0.000885
GnomAD4 exome
AF:
0.000418
AC:
459
AN:
1097369
Hom.:
3
Cov.:
31
AF XY:
0.000435
AC XY:
158
AN XY:
362817
show subpopulations
African (AFR)
AF:
0.0000379
AC:
1
AN:
26391
American (AMR)
AF:
0.000199
AC:
7
AN:
35200
Ashkenazi Jewish (ASJ)
AF:
0.0000516
AC:
1
AN:
19385
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54141
European-Finnish (FIN)
AF:
0.000749
AC:
30
AN:
40030
Middle Eastern (MID)
AF:
0.000242
AC:
1
AN:
4137
European-Non Finnish (NFE)
AF:
0.000463
AC:
390
AN:
841799
Other (OTH)
AF:
0.000629
AC:
29
AN:
46082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
20
41
61
82
102
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<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
AF:
0.000440
AC:
49
AN:
111404
Hom.:
0
Cov.:
23
AF XY:
0.000446
AC XY:
15
AN XY:
33642
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30652
American (AMR)
AF:
0.0000956
AC:
1
AN:
10463
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2640
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3515
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2649
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6060
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
216
European-Non Finnish (NFE)
AF:
0.000887
AC:
47
AN:
52996
Other (OTH)
AF:
0.000653
AC:
1
AN:
1531
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
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
Alfa
AF:
0.000727
Hom.:
5
Bravo
AF:
0.000389
EpiCase
AF:
0.000436
EpiControl
AF:
0.000533

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

GJB1: BP4, BS2 -

Aug 25, 2023
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Charcot-Marie-Tooth disease Benign:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Nov 21, 2023
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease X-linked dominant 1 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
15
DANN
Benign
0.88
PhyloP100
1.6
PromoterAI
0.019
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=300/0
polymorphism

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: rs201344743; hg19: chrX-70443552; API