rs114619322

Variant names:

• chr1-6468009-C-G
• rs114619322
• NM_020631.6:c.2827G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-6468009-C-G
• chr1-6468009-C-T

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.2827G>C​(p.Gly943Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,553,344 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G943S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (136 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (128 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.228
• Publications: 5 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=0.0025613904).
• BP6: Variant 1-6468009-C-G is Benign according to our data. Variant chr1-6468009-C-G is described in ClinVar as Benign. ClinVar VariationId is 287488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 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.2827G>C	p.Gly943Arg	missense	Exon 20 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.3034G>C	p.Gly1012Arg	missense	Exon 20 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.2938G>C	p.Gly980Arg	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.2827G>C	p.Gly943Arg	missense	Exon 20 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.2938G>C	p.Gly980Arg	missense	Exon 20 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.2938G>C	p.Gly980Arg	missense	Exon 21 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3525 AN: 152210 Hom.: 135 Cov.: 33

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00548 AC: 879 AN: 160490 AF XY: 0.00422

Gnomad AFR exome AF: 0.0813

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00249 AC: 3484 AN: 1401016 Hom.: 128 Cov.: 32 AF XY: 0.00221 AC XY: 1526 AN XY: 692058

African (AFR) AF: 0.0798 AC: 2560 AN: 32072

American (AMR) AF: 0.00612 AC: 223 AN: 36438

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 36520

South Asian (SAS) AF: 0.000274 AC: 22 AN: 80394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43632

Middle Eastern (MID) AF: 0.00610 AC: 32 AN: 5248

European-Non Finnish (NFE) AF: 0.000282 AC: 305 AN: 1083456

Other (OTH) AF: 0.00583 AC: 339 AN: 58160

GnomAD4 genome AF: 0.0232 AC: 3532 AN: 152328 Hom.: 136 Cov.: 33 AF XY: 0.0227 AC XY: 1692 AN XY: 74488

African (AFR) AF: 0.0795 AC: 3302 AN: 41558

American (AMR) AF: 0.0104 AC: 159 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68026

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00278 Hom.: 3

Bravo AF: 0.0254

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0595 AC: 252

ESP6500EA AF: 0.000479 AC: 4

ExAC AF: 0.00488 AC: 565

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	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.6
DANN	Benign	0.35
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.23
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.015
Sift	Benign	0.23	T
Sift4G	Benign	0.38	T
Polyphen		0.023	B
Vest4		0.044
MVP		0.12
MPC		0.31
ClinPred		0.0010	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.29
Mutation Taster		=97/3	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: rs114619322; hg19: chr1-6528069;