rs202049535

Variant names:

• chr1-6474170-T-C
• rs202049535
• NM_020631.6:c.440-6A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-6474170-T-C
• chr1-6474170-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020631.6(PLEKHG5):​c.440-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,613,232 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (9 hom.)
• Consequence: PLEKHG5 NM_020631.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008048
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.553
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-6474170-T-C is Benign according to our data. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6474170-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 378374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00405 (617/152304) while in subpopulation AFR AF = 0.0141 (587/41566). AF 95% confidence interval is 0.0132. There are 8 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.440-6A>G		splice_region_variant, intron_variant	Intron 6 of 20	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.440-6A>G		splice_region_variant, intron_variant	Intron 6 of 20	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152186 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.000992 AC: 247 AN: 248916 AF XY: 0.000806

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000500 AC: 731 AN: 1460928 Hom.: 9 Cov.: 38 AF XY: 0.000462 AC XY: 336 AN XY: 726730

African (AFR) AF: 0.0174 AC: 581 AN: 33476

American (AMR) AF: 0.000693 AC: 31 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52678

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111922

Other (OTH) AF: 0.00123 AC: 74 AN: 60364

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152304 Hom.: 8 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74474

African (AFR) AF: 0.0141 AC: 587 AN: 41566

American (AMR) AF: 0.00111 AC: 17 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00492

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Sep 14, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Neuronopathy, distal hereditary motor, autosomal recessive 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.81
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.15		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: rs202049535; hg19: chr1-6534230;