rs750958357

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PM4_SupportingBS1_Supporting

The NM_030962.4(SBF2):c.5014_5016delAAA(p.Lys1672del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000444 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

SBF2
NM_030962.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.72

Variant links:

Genes affected

SBF2 (HGNC:2135): (SET binding factor 2) This gene encodes a pseudophosphatase and member of the myotubularin-related protein family. This gene maps within the CMT4B2 candidate region of chromosome 11p15 and mutations in this gene have been associated with Charcot-Marie-Tooth Disease, type 4B2. [provided by RefSeq, Jul 2008]

SBF2 links:

SBF2-AS1 (HGNC:27438): (SBF2 antisense RNA 1)

SBF2-AS1 links:

LOC105369149 (HGNC:):

LOC105369149 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_030962.4. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00063 (96/152316) while in subpopulation AMR AF= 0.0017 (26/15310). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBF2	NM_030962.4 link	c.5014_5016delAAA	p.Lys1672del	conservative_inframe_deletion	Exon 36 of 40	ENST00000256190.13	NP_112224.1	Q86WG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBF2	ENST00000256190.13 link	c.5014_5016delAAA	p.Lys1672del	conservative_inframe_deletion	Exon 36 of 40	1	NM_030962.4	ENSP00000256190.8		Q86WG5-1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000457

AC:

115

AN:

251476

Hom.:

AF XY:

0.000544

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000424

AC:

620

AN:

1461818

Hom.:

AF XY:

0.000446

AC XY:

324

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000453

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000630

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000737

EpiCase

AF:

0.000600

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified along with a second SBF2 variant in a patient with spastic paraplegia and leukodystrophy, but segregation information was not provided (PMID: 30212743); Observed in apparent homozygous state in a patient with suspected Charcot-Marie-Tooth disease in the literature who also had a variant in another gene that may have been responsible for the phenotype (PMID: 36790232); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 27582484, 26392352, 30212743, 36790232) -

Charcot-Marie-Tooth disease type 4B2

Uncertain:2

Dec 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SBF2 c.5014_5016delAAA; p.Lys1672del variant (rs750958357), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 397621). This variant is found in the general population with an allele frequency of 0.046% (131/282,872 alleles) in the Genome Aggregation Database. This variant deletes a single lysine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the p.Lys1672de variant is uncertain at this time. -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Mar 13, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5014_5016delAAA (p.K1672del) alteration is located in exon 36 (coding exon 36) of the SBF2 gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.5014 and c.5016, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Peripheral neuropathy

Uncertain:1

Aug 22, 2016

Claritas Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4

Uncertain:1

Oct 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5014_5016del, results in the deletion of 1 amino acid(s) of the SBF2 protein (p.Lys1672del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750958357, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SBF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 397621). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over