1-6469122-TTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Position:

• chr1-6469122-TTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020631.6(PLEKHG5):​c.2166_2168delGGA​(p.Glu723del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 1,483,318 control chromosomes in the GnomAD database, including 2,528 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (711 hom., cov: 31)
  • Exomes 𝑓: 0.067 (1817 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.980

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-6469122-TTCC-T is Benign according to our data. Variant chr1-6469122-TTCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 194979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6469122-TTCC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.2166_2168delGGA	p.Glu723del	disruptive_inframe_deletion	19/21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.2166_2168delGGA	p.Glu723del	disruptive_inframe_deletion	19/21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 12715 AN: 145232 Hom.: 707 Cov.: 31

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.0862

GnomAD3 exomes AF: 0.0760 AC: 14943 AN: 196576 Hom.: 383 AF XY: 0.0763 AC XY: 8153 AN XY: 106916

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.00851

Gnomad SAS exome AF: 0.0956

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0753

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0673 AC: 90019 AN: 1337982 Hom.: 1817 AF XY: 0.0679 AC XY: 45140 AN XY: 664510

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0509

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.00378

Gnomad4 SAS exome AF: 0.0873

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0660

Gnomad4 OTH exome AF: 0.0739

GnomAD4 genome AF: 0.0877 AC: 12741 AN: 145336 Hom.: 711 Cov.: 31 AF XY: 0.0854 AC XY: 6065 AN XY: 71040

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0690

Gnomad4 ASJ AF: 0.0770

Gnomad4 EAS AF: 0.00407

Gnomad4 SAS AF: 0.0853

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0598

Gnomad4 OTH AF: 0.0873

Bravo AF: 0.119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	Variant summary: PLEKHG5 c.2166_2168delGGA (p.Glu723del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.076 in 196576 control chromosomes in the gnomAD database, including 383 homozygotes. The observed variant frequency is approximately 67.99 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 benign. ClinVar contains an entry for this variant (Variation ID: 194979). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Distal spinal muscular atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs113541584; hg19: chr1-6529182;