rs61749272

chr1-6468505-G-Achr1-6468505-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020631.6(PLEKHG5):c.2331C>T(p.Ser777=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.49

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=-0.82).
• BP6: Variant 1-6468505-G-A is Benign according to our data. Variant chr1-6468505-G-A is described in ClinVar as [Benign]. Clinvar id is 297946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6468505-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.2331C>T	p.Ser777=	synonymous_variant	20/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.2331C>T	p.Ser777=	synonymous_variant	20/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1387 AN: 152114 Hom.: 10 Cov.: 33

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

GnomAD3 exomes AF: 0.00931 AC: 2316 AN: 248636 Hom.: 11 AF XY: 0.00924 AC XY: 1249 AN XY: 135208

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 SAS exome AF: 0.00177

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.: 33 AF XY: 0.0121 AC XY: 8780 AN XY: 726632

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00912 AC: 1388 AN: 152232 Hom.: 10 Cov.: 33 AF XY: 0.00883 AC XY: 657 AN XY: 74426

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0110 Hom.: 8

Bravo AF: 0.00767

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PLEKHG5: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Neuronopathy, distal hereditary motor, autosomal recessive 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.22
Dann	Benign	0.67

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

LitVar

Other links and lift over

dbSNP: rs61749272; hg19: chr1-6528565; COSMIC: COSV105237437; COSMIC: COSV105237437;