chr1-6475992-G-A

Variant names:

• chr1-6475992-G-A
• rs111400494
• NM_020631.6:c.88C>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.88C>T​(p.Arg30Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00461 in 1,613,838 control chromosomes in the GnomAD database, including 27 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. R30H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (26 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.65
• Publications: 6 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=0.009325266).
• BP6: Variant 1-6475992-G-A is Benign according to our data. Variant chr1-6475992-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 245659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00268 (409/152364) while in subpopulation NFE AF = 0.00457 (311/68030). AF 95% confidence interval is 0.00415. There are 1 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 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.88C>T	p.Arg30Cys	missense	Exon 3 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.295C>T	p.Arg99Cys	missense	Exon 3 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.199C>T	p.Arg67Cys	missense	Exon 4 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.88C>T	p.Arg30Cys	missense	Exon 3 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.199C>T	p.Arg67Cys	missense	Exon 3 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.199C>T	p.Arg67Cys	missense	Exon 4 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00240 AC: 601 AN: 250318 AF XY: 0.00241

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00481 AC: 7035 AN: 1461474 Hom.: 26 Cov.: 33 AF XY: 0.00474 AC XY: 3445 AN XY: 727064

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00727 AC: 190 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86258

European-Finnish (FIN) AF: 0.000981 AC: 52 AN: 53024

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00577 AC: 6415 AN: 1111988

Other (OTH) AF: 0.00381 AC: 230 AN: 60396

GnomAD4 genome AF: 0.00268 AC: 409 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74508

African (AFR) AF: 0.000818 AC: 34 AN: 41590

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00457 AC: 311 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00344 Hom.: 1

Bravo AF: 0.00255

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	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	PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.23
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.49	P
Vest4		0.48
MVP		0.56
MPC		0.35
ClinPred		0.019	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.35
Mutation Taster		=97/3	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: rs111400494; hg19: chr1-6536052;