rs61749272
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_020631.6(PLEKHG5):c.2331C>T(p.Ser777=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,882 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0091 ( 10 hom., cov: 33)
Exomes 𝑓: 0.012 ( 161 hom. )
Consequence
PLEKHG5
NM_020631.6 synonymous
NM_020631.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -4.49
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 1-6468505-G-A is Benign according to our data. Variant chr1-6468505-G-A is described in ClinVar as [Benign]. Clinvar id is 297946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6468505-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-4.49 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00912 (1388/152232) while in subpopulation NFE AF= 0.0151 (1025/68002). AF 95% confidence interval is 0.0143. There are 10 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 10 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.2331C>T | p.Ser777= | synonymous_variant | 20/21 | ENST00000377728.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.2331C>T | p.Ser777= | synonymous_variant | 20/21 | 2 | NM_020631.6 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00912 AC: 1387AN: 152114Hom.: 10 Cov.: 33
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GnomAD3 exomes AF: 0.00931 AC: 2316AN: 248636Hom.: 11 AF XY: 0.00924 AC XY: 1249AN XY: 135208
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GnomAD4 exome AF: 0.0125 AC: 18211AN: 1460650Hom.: 161 Cov.: 33 AF XY: 0.0121 AC XY: 8780AN XY: 726632
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GnomAD4 genome AF: 0.00912 AC: 1388AN: 152232Hom.: 10 Cov.: 33 AF XY: 0.00883 AC XY: 657AN XY: 74426
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 18, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PLEKHG5: BP4, BP7, BS1, BS2 - |
Neuronopathy, distal hereditary motor, autosomal recessive 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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