1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCC

Variant names:

• chr1-6469122-TTCC-T
• rs113541584
• NM_020631.6:c.2166_2168delGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_020631.6(PLEKHG5):​c.2166_2168delGGA​(p.Glu723del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 1,483,318 control chromosomes in the GnomAD database, including 2,528 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (711 hom., cov: 31)
  • Exomes 𝑓: 0.067 (1817 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.980
• 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-TTCC-T is Benign according to our data. Variant chr1-6469122-TTCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 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.2166_2168delGGA	p.Glu723del	disruptive_inframe_deletion	Exon 19 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2373_2375delGGA	p.Glu792del	disruptive_inframe_deletion	Exon 19 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2277_2279delGGA	p.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.2166_2168delGGA	p.Glu723del	disruptive_inframe_deletion	Exon 19 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2277_2279delGGA	p.Glu760del	disruptive_inframe_deletion	Exon 19 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2277_2279delGGA	p.Glu760del	disruptive_inframe_deletion	Exon 20 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 12715 AN: 145232 Hom.: 707 Cov.: 31

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.0862

GnomAD2 exomes AF: 0.0760 AC: 14943 AN: 196576 AF XY: 0.0763

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.00851

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0753

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0673 AC: 90019 AN: 1337982 Hom.: 1817 AF XY: 0.0679 AC XY: 45140 AN XY: 664510

African (AFR) AF: 0.172 AC: 5317 AN: 30982

American (AMR) AF: 0.0509 AC: 2003 AN: 39324

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 2060 AN: 23216

East Asian (EAS) AF: 0.00378 AC: 124 AN: 32766

South Asian (SAS) AF: 0.0873 AC: 6725 AN: 76994

European-Finnish (FIN) AF: 0.0301 AC: 1402 AN: 46594

Middle Eastern (MID) AF: 0.0943 AC: 505 AN: 5358

European-Non Finnish (NFE) AF: 0.0660 AC: 67864 AN: 1028340

Other (OTH) AF: 0.0739 AC: 4019 AN: 54408

GnomAD4 genome AF: 0.0877 AC: 12741 AN: 145336 Hom.: 711 Cov.: 31 AF XY: 0.0854 AC XY: 6065 AN XY: 71040

African (AFR) AF: 0.182 AC: 6461 AN: 35554

American (AMR) AF: 0.0690 AC: 1034 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 267 AN: 3468

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5164

South Asian (SAS) AF: 0.0853 AC: 410 AN: 4804

European-Finnish (FIN) AF: 0.0182 AC: 190 AN: 10446

Middle Eastern (MID) AF: 0.107 AC: 31 AN: 290

European-Non Finnish (NFE) AF: 0.0598 AC: 4045 AN: 67672

Other (OTH) AF: 0.0873 AC: 178 AN: 2040

Alfa AF: 0.0568 Hom.: 19

Bravo AF: 0.119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Distal spinal muscular atrophy (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=85/15	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: rs113541584; hg19: chr1-6529182; COSMIC: COSV61067541; COSMIC: COSV61067541;