1-6469122-TTCCTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCCTCCTCC

Variant names:

• chr1-6469122-T-TTCC
• rs113541584
• NM_020631.6:c.2166_2168dupGGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS1_Supporting

The NM_020631.6(PLEKHG5):​c.2166_2168dupGGA​(p.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 0.000331 in 1,590,526 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 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020631.6
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000337 (49/145484) while in subpopulation EAS AF = 0.000968 (5/5164). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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_2168dupGGA	p.Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2373_2375dupGGA	p.Glu792dup	disruptive_inframe_insertion	Exon 19 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2277_2279dupGGA	p.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.2166_2168dupGGA	p.Glu723dup	disruptive_inframe_insertion	Exon 19 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2277_2279dupGGA	p.Glu760dup	disruptive_inframe_insertion	Exon 19 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2277_2279dupGGA	p.Glu760dup	disruptive_inframe_insertion	Exon 20 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes AF: 0.000337 AC: 49 AN: 145380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000384

Gnomad OTH AF: 0.000989

GnomAD2 exomes AF: 0.000351 AC: 69 AN: 196576 AF XY: 0.000383

Gnomad AFR exome AF: 0.000302

Gnomad AMR exome AF: 0.0000789

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000411

Gnomad OTH exome AF: 0.000207

GnomAD4 exome AF: 0.000331 AC: 478 AN: 1445042 Hom.: 0 Cov.: 33 AF XY: 0.000331 AC XY: 238 AN XY: 719184

African (AFR) AF: 0.000123 AC: 4 AN: 32408

American (AMR) AF: 0.000247 AC: 11 AN: 44520

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

East Asian (EAS) AF: 0.000429 AC: 17 AN: 39620

South Asian (SAS) AF: 0.000537 AC: 46 AN: 85662

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51960

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5712

European-Non Finnish (NFE) AF: 0.000344 AC: 378 AN: 1099402

Other (OTH) AF: 0.000301 AC: 18 AN: 59778

GnomAD4 genome AF: 0.000337 AC: 49 AN: 145484 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 27 AN XY: 71128

African (AFR) AF: 0.000309 AC: 11 AN: 35586

American (AMR) AF: 0.000200 AC: 3 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000968 AC: 5 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000384 AC: 26 AN: 67726

Other (OTH) AF: 0.000978 AC: 2 AN: 2044

Alfa AF: 0.000239 Hom.: 19

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Distal spinal muscular atrophy (1)
-	1	-	Inborn genetic diseases (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
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;