rs730600

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 194881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6469383-A-G is described in Lovd as [Benign].
• 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

GnomAD3 exomes AF: 0.161 AC: 40530 AN: 251454 Hom.: 5230 AF XY: 0.157 AC XY: 21327 AN XY: 135908

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 SAS exome AF: 0.176

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

Gnomad4 AFR exome AF: 0.604

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.00776

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.167

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

Gnomad4 AFR AF: 0.581

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.224

Alfa AF: 0.179 Hom.: 4478

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

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. -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

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

- -

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

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

LitVar

Other links and lift over

dbSNP: rs730600; hg19: chr1-6529443;