rs2227885
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2PP2BP4_ModerateBP6BS1
The NM_000165.5(GJA1):c.1085G>A(p.Arg362Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
GJA1
NM_000165.5 missense
NM_000165.5 missense
Scores
1
10
3
Clinical Significance
Conservation
PhyloP100: 7.65
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_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GJA1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.11708552).
BP6
?
Variant 6-121447932-G-A is Benign according to our data. Variant chr6-121447932-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16990.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000117 (171/1461652) while in subpopulation AMR AF= 0.00228 (102/44716). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4_exome. There are 93 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.1085G>A | p.Arg362Gln | missense_variant | 2/2 | ENST00000282561.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.1085G>A | p.Arg362Gln | missense_variant | 2/2 | 1 | NM_000165.5 | P1 | |
GJA1 | ENST00000647564.1 | c.1085G>A | p.Arg362Gln | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000649003.1 | c.1085G>A | p.Arg362Gln | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000650427.1 | c.1085G>A | p.Arg362Gln | missense_variant | 2/2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 151984Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000415 AC: 104AN: 250450Hom.: 0 AF XY: 0.000413 AC XY: 56AN XY: 135524
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GnomAD4 exome AF: 0.000117 AC: 171AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.000128 AC XY: 93AN XY: 727142
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Atrioventricular septal defect and common atrioventricular junction Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2001 | - - |
Hypoplastic left heart syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2001 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Published previously in the presence of a second GJA1 variant, in association with hypoplastic left heart syndrome in several unrelated individuals (Dasgupta et al., 2001); In vitro functional study showed that the p.(R362Q) variant abolishes phosphorylation of the connexin 43 channel regulation domain (Dasgupta et al., 2001); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 31564432, 22090377, 11470490, 31019026, 33432820) - |
Oculodentodigital dysplasia, autosomal recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M;M;M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D;D;D;D
Vest4
0.75
MVP
0.92
MPC
1.4
ClinPred
T
GERP RS
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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