chr1-6473355-C-G

Variant names:

• chr1-6473355-C-G
• rs146651455
• NM_020631.6:c.691G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020631.6(PLEKHG5):​c.691G>C​(p.Gly231Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G231S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371
• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.09872937).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	NM_020631.6	MANE Select	c.691G>C	p.Gly231Arg	missense	Exon 8 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.898G>C	p.Gly300Arg	missense	Exon 8 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.802G>C	p.Gly268Arg	missense	Exon 9 of 22	NP_001036128.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.691G>C	p.Gly231Arg	missense	Exon 8 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.802G>C	p.Gly268Arg	missense	Exon 8 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.802G>C	p.Gly268Arg	missense	Exon 9 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399540 Hom.: 0 Cov.: 35 AF XY: 0.00000145 AC XY: 1 AN XY: 690552

African (AFR) AF: 0.00 AC: 0 AN: 31684

American (AMR) AF: 0.00 AC: 0 AN: 35926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35874

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080098

Other (OTH) AF: 0.00 AC: 0 AN: 58048

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.37
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.15
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.57	P
Vest4		0.18
MutPred		0.28		Gain of MoRF binding (P = 0.0423)
MVP		0.19
MPC		0.84
ClinPred		0.24	T
GERP RS		-2.6
Varity_R		0.072
gMVP		0.52
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146651455; hg19: chr1-6533415;