rs776271244

Variant names:

• chr1-6477534-G-A
• rs776271244
• NM_020631.6:c.38C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-6477534-G-A
• chr1-6477534-G-C
• chr1-6477534-G-T

Variant summary

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

The NM_020631.6(PLEKHG5):​c.38C>T​(p.Pro13Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,459,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P13P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.38C>T	p.Pro13Leu	missense	Exon 2 of 21	NP_065682.2
	PLEKHG5	NM_001265593.2		c.245C>T	p.Pro82Leu	missense	Exon 2 of 21	NP_001252522.1
	PLEKHG5	NM_001042663.3		c.149C>T	p.Pro50Leu	missense	Exon 3 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.38C>T	p.Pro13Leu	missense	Exon 2 of 21	ENSP00000366957.3
	PLEKHG5	ENST00000377732.5	TSL:1	c.149C>T	p.Pro50Leu	missense	Exon 2 of 21	ENSP00000366961.1
	PLEKHG5	ENST00000400915.8	TSL:1	c.149C>T	p.Pro50Leu	missense	Exon 3 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 249226 AF XY: 0.0000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000103 AC: 15 AN: 1459400 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.37		Loss of catalytic residue at P68 (P = 0.0175)
MVP		0.82
MPC		0.27
ClinPred		0.77	D
GERP RS		4.5
PromoterAI		0.0048	Neutral
Varity_R		0.29
gMVP		0.26
Mutation Taster		=58/42	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: rs776271244; hg19: chr1-6537594;