chr1-6468255-G-A

Variant names:

• chr1-6468255-G-A
• rs148560273
• NM_020631.6:c.2581C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020631.6(PLEKHG5):​c.2581C>T​(p.Arg861Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,603,370 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R861H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.837
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058948696).
• BP6: Variant 1-6468255-G-A is Benign according to our data. Variant chr1-6468255-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00403 (614/152320) while in subpopulation AFR AF = 0.0142 (590/41572). AF 95% confidence interval is 0.0132. There are 4 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.2581C>T	p.Arg861Cys	missense	Exon 20 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2788C>T	p.Arg930Cys	missense	Exon 20 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.2692C>T	p.Arg898Cys	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.2581C>T	p.Arg861Cys	missense	Exon 20 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.2692C>T	p.Arg898Cys	missense	Exon 20 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.2692C>T	p.Arg898Cys	missense	Exon 21 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152202 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000994 AC: 238 AN: 239478 AF XY: 0.000665

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000704

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000356 AC: 517 AN: 1451050 Hom.: 3 Cov.: 32 AF XY: 0.000294 AC XY: 212 AN XY: 719954

African (AFR) AF: 0.0114 AC: 379 AN: 33336

American (AMR) AF: 0.000856 AC: 38 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000702 AC: 6 AN: 85440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52080

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5714

European-Non Finnish (NFE) AF: 0.0000416 AC: 46 AN: 1105074

Other (OTH) AF: 0.000768 AC: 46 AN: 59878

GnomAD4 genome AF: 0.00403 AC: 614 AN: 152320 Hom.: 4 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74484

African (AFR) AF: 0.0142 AC: 590 AN: 41572

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00459

ESP6500AA AF: 0.0117 AC: 51

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neuronopathy, distal hereditary motor, autosomal recessive 4 (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)
-	-	1	not specified (1)
-	-	1	PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.84
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.65
MPC		1.1
ClinPred		0.044	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.51
Mutation Taster		=100/0	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: rs148560273; hg19: chr1-6528315;