11-9858359-C-G

Position:

chr11-9858359-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_030962.4(SBF2):c.1967G>C(p.Cys656Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

SBF2
NM_030962.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.91

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:

ENSG00000255476 (HGNC:):

ENSG00000255476 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000479 (73/152270) while in subpopulation AMR AF= 0.00124 (19/15300). AF 95% confidence interval is 0.000813. There are 0 homozygotes in gnomad4. There are 33 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/exons	MANE	Protein	UniProt
SBF2	NM_030962.4 link	c.1967G>C	p.Cys656Ser	missense_variant	18/40	ENST00000256190.13	NP_112224.1	Q86WG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBF2	ENST00000256190.13 link	c.1967G>C	p.Cys656Ser	missense_variant	18/40	1	NM_030962.4	ENSP00000256190.8		Q86WG5-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000290

AC:

AN:

251390

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000389

AC:

569

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

294

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000464

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000479

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2023	The SBF2 c.1967G>C; p.Cys656Ser variant (rs138120231) is reported in the literature in an individual affected with Charcot-Marie-Tooth disease (Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 429748), and is found in the general population with an overall allele frequency of 0.028% (79/282784 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.520). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2024	Reported previously in an individual with a suspected diagnosis of CMT; however, detailed clinical information and segregation details were not provided (PMID: 32376792); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32376792) -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 31, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2021

The p.C656S variant (also known as c.1967G>C), located in coding exon 18 of the SBF2 gene, results from a G to C substitution at nucleotide position 1967. The cysteine at codon 656 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 656 of the SBF2 protein (p.Cys656Ser). This variant is present in population databases (rs138120231, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical suspicion of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 429748). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.90

MutPred

0.55

Loss of stability (P = 0.0948);

MVP

0.79

MPC

0.78

ClinPred

0.47

GERP RS

5.5

Varity_R

0.72

gMVP

0.30

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