1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCCTCCTCCTCC

Variant names:

• chr1-6469122-T-TTCCTCC
• rs113541584
• NM_020631.6:c.2163_2168dupGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_020631.6(PLEKHG5):​c.2163_2168dupGGAGGA​(p.Glu722_Glu723dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,590,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020631.6
• BP6: Variant 1-6469122-T-TTCCTCC is Benign according to our data. Variant chr1-6469122-T-TTCCTCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297950.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000054 (78/1445114) while in subpopulation AMR AF = 0.000966 (43/44520). AF 95% confidence interval is 0.000736. There are 0 homozygotes in GnomAdExome4. There are 34 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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_2168dupGGAGGA	p.Glu722_Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2370_2375dupGGAGGA	p.Glu791_Glu792dup	disruptive_inframe_insertion	Exon 19 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2274_2279dupGGAGGA	p.Glu759_Glu760dup	disruptive_inframe_insertion	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_2168dupGGAGGA	p.Glu722_Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2274_2279dupGGAGGA	p.Glu759_Glu760dup	disruptive_inframe_insertion	Exon 19 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2274_2279dupGGAGGA	p.Glu759_Glu760dup	disruptive_inframe_insertion	Exon 20 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.0000963 AC: 14 AN: 145380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000467

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.000495

GnomAD2 exomes AF: 0.000254 AC: 50 AN: 196576 AF XY: 0.000196

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000766

Gnomad FIN exome AF: 0.000120

Gnomad NFE exome AF: 0.0000555

Gnomad OTH exome AF: 0.000207

GnomAD4 exome AF: 0.0000540 AC: 78 AN: 1445114 Hom.: 0 Cov.: 33 AF XY: 0.0000473 AC XY: 34 AN XY: 719222

African (AFR) AF: 0.00 AC: 0 AN: 32406

American (AMR) AF: 0.000966 AC: 43 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 25980

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85662

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1099474

Other (OTH) AF: 0.0000669 AC: 4 AN: 59778

GnomAD4 genome AF: 0.0000963 AC: 14 AN: 145380 Hom.: 0 Cov.: 31 AF XY: 0.0000845 AC XY: 6 AN XY: 71018

African (AFR) AF: 0.00 AC: 0 AN: 35478

American (AMR) AF: 0.000467 AC: 7 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67734

Other (OTH) AF: 0.000495 AC: 1 AN: 2022

Alfa AF: 0.000120 Hom.: 19

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=84/16	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;