X-71224268-AACCGTCTTC-A
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM4PP3PP5
The NM_000166.6(GJB1):c.572_580delCCGTCTTCA(p.Thr191_Phe193del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 21)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
GJB1
NM_000166.6 disruptive_inframe_deletion
NM_000166.6 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
Publications
2 publications found
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 1Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- X-linked progressive cerebellar ataxiaInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000166.6
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000166.6.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant X-71224268-AACCGTCTTC-A is Pathogenic according to our data. Variant chrX-71224268-AACCGTCTTC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406229.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GJB1 | MANE Select | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 2 of 2 | NP_000157.1 | P08034 | ||
| GJB1 | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 2 of 2 | NP_001091111.1 | P08034 | |||
| GJB1 | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 3 of 3 | NP_001427699.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GJB1 | TSL:1 MANE Select | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 2 of 2 | ENSP00000354900.6 | P08034 | ||
| GJB1 | TSL:5 | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 2 of 2 | ENSP00000363141.1 | P08034 | ||
| GJB1 | TSL:5 | c.572_580delCCGTCTTCA | p.Thr191_Phe193del | disruptive_inframe_deletion | Exon 3 of 3 | ENSP00000407223.2 | P08034 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
21
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095115Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 361899 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1095115
Hom.:
AF XY:
AC XY:
0
AN XY:
361899
show subpopulations
African (AFR)
AF:
AC:
0
AN:
26398
American (AMR)
AF:
AC:
0
AN:
35203
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19379
East Asian (EAS)
AF:
AC:
0
AN:
30205
South Asian (SAS)
AF:
AC:
0
AN:
54101
European-Finnish (FIN)
AF:
AC:
0
AN:
37610
Middle Eastern (MID)
AF:
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
AC:
1
AN:
842010
Other (OTH)
AF:
AC:
0
AN:
46073
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
21
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
1
-
-
Charcot-Marie-Tooth Neuropathy X (1)
-
1
-
not provided (1)
-
1
-
not specified (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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