1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.980

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-TTCC-T is Benign according to our data. Variant chr1-6469122-TTCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.2166_2168delGGA	p.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.2166_2168delGGA	p.Glu723del	disruptive_inframe_deletion	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.0875

AC:

12715

AN:

145232

Hom.:

707

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0760

AC:

14943

AN:

196576

AF XY:

0.0763

show subpopulations

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 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

show subpopulations

African (AFR)

AF:

0.172

AC:

5317

AN:

30982

American (AMR)

AF:

0.0509

AC:

2003

AN:

39324

Ashkenazi Jewish (ASJ)

AF:

0.0887

AC:

2060

AN:

23216

East Asian (EAS)

AF:

0.00378

AC:

124

AN:

32766

South Asian (SAS)

AF:

0.0873

AC:

6725

AN:

76994

European-Finnish (FIN)

AF:

0.0301

AC:

1402

AN:

46594

Middle Eastern (MID)

AF:

0.0943

AC:

505

AN:

5358

European-Non Finnish (NFE)

AF:

0.0660

AC:

67864

AN:

1028340

Other (OTH)

AF:

0.0739

AC:

4019

AN:

54408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4468

8936

13404

17872

22340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2632

5264

7896

10528

13160

<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:

0.0877

AC:

12741

AN:

145336

Hom.:

711

Cov.:

AF XY:

0.0854

AC XY:

6065

AN XY:

71040

show subpopulations

African (AFR)

AF:

0.182

AC:

6461

AN:

35554

American (AMR)

AF:

0.0690

AC:

1034

AN:

14990

Ashkenazi Jewish (ASJ)

AF:

0.0770

AC:

267

AN:

3468

East Asian (EAS)

AF:

0.00407

AC:

AN:

5164

South Asian (SAS)

AF:

0.0853

AC:

410

AN:

4804

European-Finnish (FIN)

AF:

0.0182

AC:

190

AN:

10446

Middle Eastern (MID)

AF:

0.107

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0598

AC:

4045

AN:

67672

Other (OTH)

AF:

0.0873

AC:

178

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

552

1103

1655

2206

2758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0568

Hom.:

Bravo

AF:

0.119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Distal spinal muscular atrophy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.98

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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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