1-6469383-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020631.6(PLEKHG5):c.2001T>C(p.Ser667Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,862 control chromosomes in the GnomAD database, including 29,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 8249 hom., cov: 33)

Exomes 𝑓: 0.15 ( 20817 hom. )

Consequence

PLEKHG5
NM_020631.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.193

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 1-6469383-A-G is Benign according to our data. Variant chr1-6469383-A-G is described in ClinVar as Benign. ClinVar VariationId is 194881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.193 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.2001T>C	p.Ser667Ser	synonymous_variant	Exon 18 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.2001T>C	p.Ser667Ser	synonymous_variant	Exon 18 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39905

AN:

152104

Hom.:

8213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.581

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.223

GnomAD2 exomes

AF:

0.161

AC:

40530

AN:

251454

AF XY:

0.157

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.0936

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00408

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.149

AC:

217782

AN:

1461640

Hom.:

20817

Cov.:

AF XY:

0.149

AC XY:

108458

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.604

AC:

20231

AN:

33472

American (AMR)

AF:

0.102

AC:

4548

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3661

AN:

26136

East Asian (EAS)

AF:

0.00776

AC:

308

AN:

39700

South Asian (SAS)

AF:

0.176

AC:

15153

AN:

86234

European-Finnish (FIN)

AF:

0.166

AC:

8855

AN:

53340

Middle Eastern (MID)

AF:

0.216

AC:

1247

AN:

5768

European-Non Finnish (NFE)

AF:

0.138

AC:

153689

AN:

1111874

Other (OTH)

AF:

0.167

AC:

10090

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

11310

22621

33931

45242

56552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5582

11164

16746

22328

27910

<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:

0.263

AC:

39996

AN:

152222

Hom.:

8249

Cov.:

AF XY:

0.260

AC XY:

19384

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.581

AC:

24124

AN:

41496

American (AMR)

AF:

0.158

AC:

2419

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

474

AN:

3470

East Asian (EAS)

AF:

0.00502

AC:

AN:

5180

South Asian (SAS)

AF:

0.178

AC:

859

AN:

4830

European-Finnish (FIN)

AF:

0.157

AC:

1669

AN:

10612

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9737

AN:

68014

Other (OTH)

AF:

0.224

AC:

475

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1250

2500

3749

4999

6249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.182

Hom.:

5967

Bravo

AF:

0.275

Asia WGS

AF:

0.146

AC:

506

AN:

3478

EpiCase

AF:

0.149

EpiControl

AF:

0.144

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease recessive intermediate C

Benign:1

Oct 25, 2021

Genome-Nilou Lab

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.0

(source)

DANN

Benign

0.58

PhyloP100

-0.19

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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