1-6469122-T-TTCCTCCTCCTCC

Variant names:

• chr1-6469122-T-TTCCTCCTCCTCC
• rs113541584
• NM_020631.6:c.2157_2168dupGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_020631.6(PLEKHG5):​c.2157_2168dupGGAGGAGGAGGA​(p.Glu720_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 0.000017 in 1,590,502 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020631.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.2157_2168dupGGAGGAGGAGGA	p.Glu720_Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.2157_2168dupGGAGGAGGAGGA	p.Glu720_Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.0000481 AC: 7 AN: 145380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000286

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 4 AN: 196576 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000600

Gnomad NFE exome AF: 0.0000333

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1445122 Hom.: 0 Cov.: 33 AF XY: 0.0000167 AC XY: 12 AN XY: 719224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32410

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

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

European-Finnish (FIN) AF: 0.000269 AC: 14 AN: 51962

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

European-Non Finnish (NFE) AF: 0.00000455 AC: 5 AN: 1099478

Other (OTH) AF: 0.0000167 AC: 1 AN: 59778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000481 AC: 7 AN: 145380 Hom.: 0 Cov.: 31 AF XY: 0.0000704 AC XY: 5 AN XY: 71018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.000286 AC: 3 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: 0.00 AC: 0 AN: 2022

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000546), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000160 Hom.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;