1-6474033-G-C

Variant names:

• chr1-6474033-G-C
• rs183712624
• NM_020631.6:c.571C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020631.6(PLEKHG5):​c.571C>G​(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000826 in 1,210,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R191Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 3 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4050678).

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.571C>G	p.Arg191Gly	missense	Exon 7 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.778C>G	p.Arg260Gly	missense	Exon 7 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.682C>G	p.Arg228Gly	missense	Exon 8 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.571C>G	p.Arg191Gly	missense	Exon 7 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.682C>G	p.Arg228Gly	missense	Exon 7 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.682C>G	p.Arg228Gly	missense	Exon 8 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235596 AF XY: 0.00000775

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.26e-7 AC: 1 AN: 1210816 Hom.: 0 Cov.: 38 AF XY: 0.00000167 AC XY: 1 AN XY: 599470

African (AFR) AF: 0.00 AC: 0 AN: 26318

American (AMR) AF: 0.0000271 AC: 1 AN: 36920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16994

East Asian (EAS) AF: 0.00 AC: 0 AN: 17526

South Asian (SAS) AF: 0.00 AC: 0 AN: 82150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 950946

Other (OTH) AF: 0.00 AC: 0 AN: 43920

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Benign	0.053	T
Sift4G	Uncertain	0.011	D
Polyphen		0.96	D
Vest4		0.60
MutPred		0.28		Loss of MoRF binding (P = 0.0183)
MVP		0.51
MPC		0.40
ClinPred		0.89	D
GERP RS		0.78
Varity_R		0.17
gMVP		0.61
Mutation Taster		=78/22	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: rs183712624; hg19: chr1-6534093;