rs104893966
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_000165.5(GJA1):c.581A>C(p.His194Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
GJA1
NM_000165.5 missense
NM_000165.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
GJA1 (HGNC:4274): (gap junction protein alpha 1) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]
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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 30) in uniprot entity CXA1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000165.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GJA1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
?
Variant 6-121447428-A-C is Pathogenic according to our data. Variant chr6-121447428-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 16992.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.581A>C | p.His194Pro | missense_variant | 2/2 | ENST00000282561.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.581A>C | p.His194Pro | missense_variant | 2/2 | 1 | NM_000165.5 | P1 | |
GJA1 | ENST00000647564.1 | c.581A>C | p.His194Pro | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000649003.1 | c.581A>C | p.His194Pro | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000650427.1 | c.581A>C | p.His194Pro | missense_variant | 2/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Oculodentodigital dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2005 | - - |
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
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;M;M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D;D;D;D
Vest4
0.92
MutPred
Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);
MVP
0.98
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at