1-6469065-G-T

Variant names:

• chr1-6469065-G-T
• rs370761668
• NM_020631.6:c.2226C>A

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.2226C>A​(p.Ser742Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,300 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. Synonymous variant affecting the same amino acid position (i.e. S742S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331
• 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=0.116283715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.2226C>A	p.Ser742Arg	missense_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.2226C>A	p.Ser742Arg	missense_variant	Exon 19 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461300 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;.;D;D;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;L;.
PhyloP100		0.33
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;D
REVEL	Uncertain	0.33
Sift	Benign	0.045	D;T;T;D;D;T;T;T;D;D
Sift4G	Uncertain	0.054	T;T;T;T;T;T;T;T;T;T
Polyphen		0.96, 0.93, 0.015	.;.;.;.;D;D;.;.;P;B
Vest4		0.41
MutPred		0.38		.;.;.;.;.;.;.;.;Loss of phosphorylation at S798 (P = 0.0013);.;
MVP		0.29
MPC		0.67
ClinPred		0.73	D
GERP RS		1.5
PromoterAI		-0.019	Neutral
Varity_R		0.049
gMVP		0.42
Mutation Taster		=73/27	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: rs370761668; hg19: chr1-6529125;