1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCC

Variant names:

• chr1-6469122-TTCCTCC-T
• rs113541584
• NM_020631.6:c.2163_2168delGGAGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_020631.6(PLEKHG5):​c.2163_2168delGGAGGA​(p.Glu722_Glu723del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00862 in 1,588,674 control chromosomes in the GnomAD database, including 99 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E721del) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (35 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (64 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.94
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020631.6
• BP6: Variant 1-6469122-TTCCTCC-T is Benign according to our data. Variant chr1-6469122-TTCCTCC-T is described in ClinVar as Benign. ClinVar VariationId is 194977.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 = 0.014 (2041/145478) while in subpopulation AFR AF = 0.0316 (1126/35584). AF 95% confidence interval is 0.0301. There are 35 homozygotes in GnomAd4. There are 1017 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.2163_2168delGGAGGA	p.Glu722_Glu723del	disruptive_inframe_deletion	Exon 19 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2370_2375delGGAGGA	p.Glu791_Glu792del	disruptive_inframe_deletion	Exon 19 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2274_2279delGGAGGA	p.Glu759_Glu760del	disruptive_inframe_deletion	Exon 20 of 22	NP_001036128.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.2163_2168delGGAGGA	p.Glu722_Glu723del	disruptive_inframe_deletion	Exon 19 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2274_2279delGGAGGA	p.Glu759_Glu760del	disruptive_inframe_deletion	Exon 19 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2274_2279delGGAGGA	p.Glu759_Glu760del	disruptive_inframe_deletion	Exon 20 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2037 AN: 145374 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00915

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00927

Gnomad SAS AF: 0.00956

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.0114

GnomAD2 exomes AF: 0.0115 AC: 2258 AN: 196576 AF XY: 0.0110

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00903

Gnomad ASJ exome AF: 0.00711

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00906

Gnomad NFE exome AF: 0.00986

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00808 AC: 11658 AN: 1443196 Hom.: 64 AF XY: 0.00801 AC XY: 5753 AN XY: 718176

African (AFR) AF: 0.0287 AC: 922 AN: 32140

American (AMR) AF: 0.00726 AC: 323 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 127 AN: 25930

East Asian (EAS) AF: 0.00573 AC: 227 AN: 39620

South Asian (SAS) AF: 0.00796 AC: 680 AN: 85394

European-Finnish (FIN) AF: 0.00766 AC: 398 AN: 51932

Middle Eastern (MID) AF: 0.0114 AC: 65 AN: 5704

European-Non Finnish (NFE) AF: 0.00757 AC: 8312 AN: 1098304

Other (OTH) AF: 0.0101 AC: 604 AN: 59684

GnomAD4 genome AF: 0.0140 AC: 2041 AN: 145478 Hom.: 35 Cov.: 31 AF XY: 0.0143 AC XY: 1017 AN XY: 71126

African (AFR) AF: 0.0316 AC: 1126 AN: 35584

American (AMR) AF: 0.00913 AC: 137 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00910 AC: 47 AN: 5164

South Asian (SAS) AF: 0.00916 AC: 44 AN: 4806

European-Finnish (FIN) AF: 0.00867 AC: 91 AN: 10490

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00814 AC: 551 AN: 67724

Other (OTH) AF: 0.0127 AC: 26 AN: 2044

Alfa AF: 0.00483 Hom.: 19

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
PhyloP100		3.9
Mutation Taster		=198/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113541584; hg19: chr1-6529182; COSMIC: COSV61068457; COSMIC: COSV61068457;