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.

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.2160_2163delGGAGinsA	p.Glu721del	conservative_inframe_deletion synonymous	Exon 19 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2367_2370delGGAGinsA	p.Glu790del	conservative_inframe_deletion synonymous	Exon 19 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.2271_2274delGGAGinsA	p.Glu758del	conservative_inframe_deletion synonymous	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.2160_2163delGGAGinsA	p.Glu721del	conservative_inframe_deletion synonymous	Exon 19 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.2271_2274delGGAGinsA	p.Glu758del	conservative_inframe_deletion synonymous	Exon 19 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.2271_2274delGGAGinsA	p.Glu758del	conservative_inframe_deletion synonymous	Exon 20 of 22	ENSP00000383706.4

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;