Genetic Variant NM_020631.6:c.2166_2168dupGGA (chr1-6469122-T-TTCC) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_020631.6(PLEKHG5):c.2166_2168dupGGA(p.Glu723dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,590,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.980

Variant links:

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]

PLEKHG5 links:

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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;

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000337 (49/145484) while in subpopulation EAS AF= 0.000968 (5/5164). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.2166_2168dupGGA	p.Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	ENST00000377728.8	NP_065682.2	O94827-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 link	c.2166_2168dupGGA	p.Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.000337

AC:

AN:

145380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000384

Gnomad OTH

AF:

0.000989

GnomAD3 exomes

AF:

0.000351

AC:

AN:

196576

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

106916

show subpopulations

Gnomad AFR exome

AF:

0.000302

Gnomad AMR exome

AF:

0.0000789

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000613

Gnomad SAS exome

AF:

0.000683

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000411

Gnomad OTH exome

AF:

0.000207

GnomAD4 exome

AF:

0.000331

AC:

478

AN:

1445042

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

238

AN XY:

719184

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000429

Gnomad4 SAS exome

AF:

0.000537

Gnomad4 FIN exome

AF:

0.0000385

Gnomad4 NFE exome

AF:

0.000344

Gnomad4 OTH exome

AF:

0.000301

GnomAD4 genome

AF:

0.000337

AC:

AN:

145484

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

AN XY:

71128

show subpopulations

Gnomad4 AFR

AF:

0.000309

Gnomad4 AMR

AF:

0.000200

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000968

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000953

Gnomad4 NFE

AF:

0.000384

Gnomad4 OTH

AF:

0.000978

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 25, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLEKHG5 c.2166_2168dupGGA; p.Glu723dup variant (rs113541584), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 297949). This variant is found in the general population with an overall allele frequency of 0.033% (75/226000 alleles) in the Genome Aggregation Database. This variant deletes a single glutamate residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. -

Distal spinal muscular atrophy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2166_2168dupGGA variant (also known as p.E723dup) is located in coding exon 18 of the PLEKHG5 gene. This variant results from an in-frame duplication of 3 nucleotides at positions 2166 to 2168. This results in the duplication of a glutamic acid residue at codon 723. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C

Uncertain:1

Jun 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant has uncertain impact on PLEKHG5 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. This variant has not been reported in the literature in individuals with a PLEKHG5-related disease. ClinVar contains an entry for this variant (Variation ID: 297949). This variant is present in population databases (rs756583787, ExAC 0.07%). This variant, c.2166_2168dupGGA, results in the insertion of 1 amino acid to the PLEKHG5 protein (p.Glu723dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over