chr1-6468138-G-A

Variant names:

• chr1-6468138-G-A
• rs750132016
• NM_020631.6:c.2698C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020631.6(PLEKHG5):​c.2698C>T​(p.Arg900Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000634 in 1,419,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R900H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.21
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020631.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.2698C>T	p.Arg900Cys	missense	Exon 20 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2905C>T	p.Arg969Cys	missense	Exon 20 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.2809C>T	p.Arg937Cys	missense	Exon 21 of 22	NP_001036128.2	O94827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.2698C>T	p.Arg900Cys	missense	Exon 20 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.2809C>T	p.Arg937Cys	missense	Exon 20 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.2809C>T	p.Arg937Cys	missense	Exon 21 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000146 AC: 3 AN: 204948 AF XY: 0.0000179

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000634 AC: 9 AN: 1419002 Hom.: 0 Cov.: 32 AF XY: 0.00000999 AC XY: 7 AN XY: 700782

African (AFR) AF: 0.00 AC: 0 AN: 32440

American (AMR) AF: 0.0000493 AC: 2 AN: 40534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23178

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00000550 AC: 6 AN: 1090152

Other (OTH) AF: 0.00 AC: 0 AN: 58274

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.35		Loss of solvent accessibility (P = 0.002)
MVP		0.72
MPC		1.1
ClinPred		0.80	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.47
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs750132016; hg19: chr1-6528198;