rs750540794
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001110219.3(GJB6):c.179G>T(p.Cys60Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,968 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
GJB6
NM_001110219.3 missense
NM_001110219.3 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 7.86
Genes affected
GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a topological_domain Extracellular (size 29) in uniprot entity CXB6_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001110219.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.996
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB6 | NM_001110219.3 | c.179G>T | p.Cys60Phe | missense_variant | 5/5 | ENST00000647029.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB6 | ENST00000647029.1 | c.179G>T | p.Cys60Phe | missense_variant | 5/5 | NM_001110219.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251452Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135894
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461788Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727180
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hidrotic ectodermal dysplasia syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;H;H;H;H;H;H;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;.;.;D;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D;.;.;D;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;.;D;D;.;.;D;.;.;.;.;.;.;.
Polyphen
D;D;D;D;D;D;D;D;D;D;D;.;.;.
Vest4
MutPred
Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);Loss of ubiquitination at K61 (P = 0.0896);
MVP
MPC
0.62
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at