rs386628081
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_020631.6(PLEKHG5):c.2160_2163delinsA(p.Glu723del) variant causes a protein altering change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
PLEKHG5
NM_020631.6 protein_altering
NM_020631.6 protein_altering
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.09
Genes affected
PLEKHG5 (HGNC:29105): (pleckstrin homology and RhoGEF domain containing G5) This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 1-6469128-CTCC-T is Benign according to our data. Variant chr1-6469128-CTCC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2501239.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.2160_2163delinsA | p.Glu723del | protein_altering_variant | 19/21 | ENST00000377728.8 | NP_065682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.2160_2163delinsA | p.Glu723del | protein_altering_variant | 19/21 | 2 | NM_020631.6 | ENSP00000366957 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 16, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2023 | Variant summary: PLEKHG5 c.2160_2163delinsA (p.Glu723del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was not found in gnomAD but the same residual change (p.Glu72del) at a frequency of 0.088 in 145232 control chromosomes, predominantly at a frequency of 0.18 within the African or African-American subpopulation in the gnomAD database, including 509 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 161 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLEKHG5 causing Distal Spinal Muscular Atrophy, Autosomal Recessive 4 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2160_2163delinsA in individuals affected with Distal Spinal Muscular Atrophy, Autosomal Recessive 4 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at