rs730600

Variant names:

• chr1-6469383-A-G
• rs730600
• NM_020631.6:c.2001T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.193
• Publications: 13 publications found

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

ACMG classification

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	c.2001T>C	p.Ser667Ser	synonymous_variant	Exon 18 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.2001T>C	p.Ser667Ser	synonymous_variant	Exon 18 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39905 AN: 152104 Hom.: 8213 Cov.: 33

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

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.: 35 AF XY: 0.149 AC XY: 108458 AN XY: 727124

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

GnomAD4 genome AF: 0.263 AC: 39996 AN: 152222 Hom.: 8249 Cov.: 33 AF XY: 0.260 AC XY: 19384 AN XY: 74438

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: 26 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: 68 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9737 AN: 68014

Other (OTH) AF: 0.224 AC: 475 AN: 2116

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

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
DANN	Benign	0.58
PhyloP100		-0.19
PromoterAI		0.017	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs730600; hg19: chr1-6529443;