1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_020631.6(PLEKHG5):c.2163_2168delGGAGGA(p.Glu722_Glu723del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00862 in 1,588,674 control chromosomes in the GnomAD database, including 99 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E721del) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 35 hom., cov: 31)

Exomes 𝑓: 0.0081 ( 64 hom. )

Consequence

PLEKHG5
NM_020631.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.94

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

neuromuscular disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease recessive intermediate C
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
neuronopathy, distal hereditary motor, autosomal recessive 4
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_020631.6

BP6

Variant 1-6469122-TTCCTCC-T is Benign according to our data. Variant chr1-6469122-TTCCTCC-T is described in ClinVar as Benign. ClinVar VariationId is 194977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2041/145478) while in subpopulation AFR AF = 0.0316 (1126/35584). AF 95% confidence interval is 0.0301. There are 35 homozygotes in GnomAd4. There are 1017 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.2163_2168delGGAGGA	p.Glu722_Glu723del	disruptive_inframe_deletion	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.2163_2168delGGAGGA	p.Glu722_Glu723del	disruptive_inframe_deletion	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2037

AN:

145374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0317

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00915

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00927

Gnomad SAS

AF:

0.00956

Gnomad FIN

AF:

0.00867

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.0114

GnomAD2 exomes

AF:

0.0115

AC:

2258

AN:

196576

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.00903

Gnomad ASJ exome

AF:

0.00711

Gnomad EAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.00906

Gnomad NFE exome

AF:

0.00986

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00808

AC:

11658

AN:

1443196

Hom.:

AF XY:

0.00801

AC XY:

5753

AN XY:

718176

show subpopulations

African (AFR)

AF:

0.0287

AC:

922

AN:

32140

American (AMR)

AF:

0.00726

AC:

323

AN:

44488

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

127

AN:

25930

East Asian (EAS)

AF:

0.00573

AC:

227

AN:

39620

South Asian (SAS)

AF:

0.00796

AC:

680

AN:

85394

European-Finnish (FIN)

AF:

0.00766

AC:

398

AN:

51932

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00757

AC:

8312

AN:

1098304

Other (OTH)

AF:

0.0101

AC:

604

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

609

1218

1826

2435

3044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0140

AC:

2041

AN:

145478

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1017

AN XY:

71126

show subpopulations

African (AFR)

AF:

0.0316

AC:

1126

AN:

35584

American (AMR)

AF:

0.00913

AC:

137

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00910

AC:

AN:

5164

South Asian (SAS)

AF:

0.00916

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00867

AC:

AN:

10490

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00814

AC:

551

AN:

67724

Other (OTH)

AF:

0.0127

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00483

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 31, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLEKHG5-related disorder

Benign:1

Sep 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=198/2

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over