rs386628081

Variant names:

• chr1-6469128-CTCC-T
• rs386628081
• NM_020631.6:c.2160_2163delGGAGinsA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_020631.6(PLEKHG5):​c.2160_2163delGGAGinsA​(p.Glu721del) variant causes a conservative inframe deletion, synonymous change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E720E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHG5 NM_020631.6 conservative_inframe_deletion, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.09
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_020631.6
• BP6: Variant 1-6469128-CTCC-T is Benign according to our data. Variant chr1-6469128-CTCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2501239.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.2160_2163delGGAGinsA	p.Glu721del	conservative_inframe_deletion, synonymous_variant	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.2160_2163delGGAGinsA	p.Glu721del	conservative_inframe_deletion, synonymous_variant	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Apr 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Mar 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PLEKHG5 c.2160_2163delinsA (p.Glu723del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was not found in gnomAD but the same residual change (p.Glu72del) at a frequency of 0.088 in 145232 control chromosomes, predominantly at a frequency of 0.18 within the African or African-American subpopulation in the gnomAD database, including 509 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 161 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLEKHG5 causing Distal Spinal Muscular Atrophy, Autosomal Recessive 4 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2160_2163delinsA in individuals affected with Distal Spinal Muscular Atrophy, Autosomal Recessive 4 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1

Splicing

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

Other links and lift over

dbSNP: rs386628081; hg19: chr1-6529188;