chr1-6468260-C-T

Variant names:

• chr1-6468260-C-T
• rs61737997
• NM_020631.6:c.2576G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020631.6(PLEKHG5):​c.2576G>A​(p.Arg859His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,603,952 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R859C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (151 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (141 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.702
• Publications: 2 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=0.0015694499).
• BP6: Variant 1-6468260-C-T is Benign according to our data. Variant chr1-6468260-C-T is described in ClinVar as Benign. ClinVar VariationId is 287487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

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.2576G>A	p.Arg859His	missense	Exon 20 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2783G>A	p.Arg928His	missense	Exon 20 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.2687G>A	p.Arg896His	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.2576G>A	p.Arg859His	missense	Exon 20 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.2687G>A	p.Arg896His	missense	Exon 20 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.2687G>A	p.Arg896His	missense	Exon 21 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3682 AN: 151998 Hom.: 150 Cov.: 33

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.00617 AC: 1475 AN: 239230 AF XY: 0.00467

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000411

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00261 AC: 3790 AN: 1451836 Hom.: 141 Cov.: 32 AF XY: 0.00229 AC XY: 1652 AN XY: 720490

African (AFR) AF: 0.0829 AC: 2764 AN: 33342

American (AMR) AF: 0.00622 AC: 276 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.000304 AC: 26 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52046

Middle Eastern (MID) AF: 0.00718 AC: 41 AN: 5712

European-Non Finnish (NFE) AF: 0.000293 AC: 324 AN: 1105698

Other (OTH) AF: 0.00594 AC: 356 AN: 59920

GnomAD4 genome AF: 0.0243 AC: 3690 AN: 152116 Hom.: 151 Cov.: 33 AF XY: 0.0238 AC XY: 1766 AN XY: 74354

African (AFR) AF: 0.0832 AC: 3450 AN: 41472

American (AMR) AF: 0.0107 AC: 163 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67976

Other (OTH) AF: 0.0171 AC: 36 AN: 2108

Alfa AF: 0.0108 Hom.: 32

Bravo AF: 0.0265

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0713 AC: 312

ESP6500EA AF: 0.000701 AC: 6

ExAC AF: 0.00740 AC: 896

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.70
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.023
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.016	D
Polyphen		0.27	B
Vest4		0.21
MVP		0.61
MPC		0.96
ClinPred		0.026	T
GERP RS		3.9
Varity_R		0.078
gMVP		0.49
Mutation Taster		=99/1	polymorphism (auto)

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: rs61737997; hg19: chr1-6528320;