chr11-9785302-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_030962.4(SBF2):c.5054C>G(p.Ser1685Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1685L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SBF2
NM_030962.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.98

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03893757).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00042 (64/152312) while in subpopulation AFR AF = 0.00149 (62/41562). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030962.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SBF2	NM_030962.4	MANE Select	c.5054C>G	p.Ser1685Trp	missense	Exon 37 of 40	NP_112224.1
SBF2	NM_001386339.1		c.5150C>G	p.Ser1717Trp	missense	Exon 38 of 41	NP_001373268.1
SBF2	NM_001424318.1		c.5090C>G	p.Ser1697Trp	missense	Exon 38 of 41	NP_001411247.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SBF2	ENST00000256190.13	TSL:1 MANE Select	c.5054C>G	p.Ser1685Trp	missense	Exon 37 of 40	ENSP00000256190.8
SBF2	ENST00000689128.1		c.5150C>G	p.Ser1717Trp	missense	Exon 38 of 41	ENSP00000509587.1
SBF2	ENST00000675281.2		c.5129C>G	p.Ser1710Trp	missense	Exon 38 of 41	ENSP00000502491.1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000954

AC:

AN:

251472

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111910

Other (OTH)

AF:

0.000132

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000420

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41562

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000198

Hom.:

Bravo

AF:

0.000495

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5054C>G (p.S1685W) alteration is located in exon 37 (coding exon 37) of the SBF2 gene. This alteration results from a C to G substitution at nucleotide position 5054, causing the serine (S) at amino acid position 1685 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Charcot-Marie-Tooth disease type 4B2

Uncertain:1

May 15, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

not provided

Uncertain:1

Dec 19, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Charcot-Marie-Tooth disease type 4

Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 1685 of the SBF2 protein (p.Ser1685Trp). This variant is present in population databases (rs148468522, gnomAD 0.1%). 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: 426520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SBF2 protein function with a negative predictive value of 80%. 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.71

M_CAP

Benign

0.027

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

3.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.3

REVEL

Benign

0.075

Sift

Benign

0.036

Sift4G

Uncertain

0.012

Polyphen

0.90

Vest4

0.43

MVP

0.38

MPC

0.56

ClinPred

0.092

GERP RS

2.2

Varity_R

0.034

gMVP

0.58

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over