1-6468202-G-A

Variant names:

• chr1-6468202-G-A
• rs367560509
• NM_020631.6:c.2634C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_020631.6(PLEKHG5):​c.2634C>T​(p.Ser878Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,576,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: PLEKHG5 NM_020631.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -7.09
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-6468202-G-A is Benign according to our data. Variant chr1-6468202-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297937.
• BP7: Synonymous conserved (PhyloP=-7.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152352) while in subpopulation SAS AF = 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 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.2634C>T	p.Ser878Ser	synonymous	Exon 20 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.2841C>T	p.Ser947Ser	synonymous	Exon 20 of 21	NP_001252522.1	A0A804EMX3
	PLEKHG5	NM_001042663.3		c.2745C>T	p.Ser915Ser	synonymous	Exon 21 of 22	NP_001036128.2	O94827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.2634C>T	p.Ser878Ser	synonymous	Exon 20 of 21	ENSP00000366957.3	O94827-5
	PLEKHG5	ENST00000377732.5	TSL:1	c.2745C>T	p.Ser915Ser	synonymous	Exon 20 of 21	ENSP00000366961.1	O94827-3
	PLEKHG5	ENST00000400915.8	TSL:1	c.2745C>T	p.Ser915Ser	synonymous	Exon 21 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000399 AC: 88 AN: 220786 AF XY: 0.000425

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000514

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000950

GnomAD4 exome AF: 0.000223 AC: 318 AN: 1424538 Hom.: 1 Cov.: 32 AF XY: 0.000257 AC XY: 181 AN XY: 703312

African (AFR) AF: 0.000153 AC: 5 AN: 32640

American (AMR) AF: 0.00107 AC: 45 AN: 42092

Ashkenazi Jewish (ASJ) AF: 0.000422 AC: 10 AN: 23680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.000928 AC: 75 AN: 80788

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51048

Middle Eastern (MID) AF: 0.00162 AC: 9 AN: 5564

European-Non Finnish (NFE) AF: 0.000134 AC: 146 AN: 1090916

Other (OTH) AF: 0.000461 AC: 27 AN: 58574

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74502

African (AFR) AF: 0.000144 AC: 6 AN: 41582

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000298

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal recessive 4 (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
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.077
DANN	Benign	0.88
PhyloP100		-7.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs367560509; hg19: chr1-6528262; COSMIC: COSV107418852; COSMIC: COSV107418852;