NM_020631.6:c.2331C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020631.6(PLEKHG5):c.2331C>T(p.Ser777Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,882 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 10 hom., cov: 33)

Exomes 𝑓: 0.012 ( 161 hom. )

Consequence

PLEKHG5
NM_020631.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.49

Publications

2 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=-0.82).

BP6

Variant 1-6468505-G-A is Benign according to our data. Variant chr1-6468505-G-A is described in ClinVar as Benign. ClinVar VariationId is 297946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00912 (1388/152232) while in subpopulation NFE AF = 0.0151 (1025/68002). AF 95% confidence interval is 0.0143. There are 10 homozygotes in GnomAd4. There are 657 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.2331C>T	p.Ser777Ser	synonymous_variant	Exon 20 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.2331C>T	p.Ser777Ser	synonymous_variant	Exon 20 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1387

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00931

AC:

2316

AN:

248636

AF XY:

0.00924

show subpopulations

Gnomad AFR exome

AF:

0.00196

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.00531

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0100

GnomAD4 exome

AF:

0.0125

AC:

18211

AN:

1460650

Hom.:

161

Cov.:

AF XY:

0.0121

AC XY:

8780

AN XY:

726632

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33478

American (AMR)

AF:

0.00329

AC:

147

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

143

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00205

AC:

177

AN:

86256

European-Finnish (FIN)

AF:

0.0165

AC:

866

AN:

52382

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0146

AC:

16199

AN:

1111838

Other (OTH)

AF:

0.0100

AC:

604

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1177

2354

3530

4707

5884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.00912

AC:

1388

AN:

152232

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

657

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41530

American (AMR)

AF:

0.00196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00270

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0159

AC:

169

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1025

AN:

68002

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0110

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLEKHG5: BP4, BP7, BS1, BS2 -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Benign:1

Jan 12, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.22

(source)

DANN

Benign

0.67

PhyloP100

-4.5

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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