rs730600

Variant names:

• chr1-6469383-A-G
• rs730600
• NM_020631.6:c.2001T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001265593.2(PLEKHG5):​c.2208T>C​(p.Ser736Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,862 control chromosomes in the GnomAD database, including 29,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (8249 hom., cov: 33)
  • Exomes 𝑓: 0.15 (20817 hom.)
• Consequence: PLEKHG5 NM_001265593.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.193
• Publications: 13 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, autosomal recessive 4

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-6469383-A-G is Benign according to our data. Variant chr1-6469383-A-G is described in ClinVar as Benign. ClinVar VariationId is 194881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.193 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001265593.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.2001T>C	p.Ser667Ser	synonymous	Exon 18 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2208T>C	p.Ser736Ser	synonymous	Exon 18 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2112T>C	p.Ser704Ser	synonymous	Exon 19 of 22	NP_001036128.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.2001T>C	p.Ser667Ser	synonymous	Exon 18 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2112T>C	p.Ser704Ser	synonymous	Exon 18 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2112T>C	p.Ser704Ser	synonymous	Exon 19 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39905 AN: 152104 Hom.: 8213 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.161 AC: 40530 AN: 251454 AF XY: 0.157

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.0936

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00408

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.149 AC: 217782 AN: 1461640 Hom.: 20817 Cov.: 35 AF XY: 0.149 AC XY: 108458 AN XY: 727124

African (AFR) AF: 0.604 AC: 20231 AN: 33472

American (AMR) AF: 0.102 AC: 4548 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3661 AN: 26136

East Asian (EAS) AF: 0.00776 AC: 308 AN: 39700

South Asian (SAS) AF: 0.176 AC: 15153 AN: 86234

European-Finnish (FIN) AF: 0.166 AC: 8855 AN: 53340

Middle Eastern (MID) AF: 0.216 AC: 1247 AN: 5768

European-Non Finnish (NFE) AF: 0.138 AC: 153689 AN: 1111874

Other (OTH) AF: 0.167 AC: 10090 AN: 60392

GnomAD4 genome AF: 0.263 AC: 39996 AN: 152222 Hom.: 8249 Cov.: 33 AF XY: 0.260 AC XY: 19384 AN XY: 74438

African (AFR) AF: 0.581 AC: 24124 AN: 41496

American (AMR) AF: 0.158 AC: 2419 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5180

South Asian (SAS) AF: 0.178 AC: 859 AN: 4830

European-Finnish (FIN) AF: 0.157 AC: 1669 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9737 AN: 68014

Other (OTH) AF: 0.224 AC: 475 AN: 2116

Alfa AF: 0.182 Hom.: 5967

Bravo AF: 0.275

Asia WGS AF: 0.146 AC: 506 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.144

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neuronopathy, distal hereditary motor, autosomal recessive 4 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease recessive intermediate C (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
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.0
DANN	Benign	0.58
PhyloP100		-0.19
PromoterAI		0.017	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730600; hg19: chr1-6529443;