Genetic Variant SBF2:p.Val443Ile (chr11-9989565-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030962.4(SBF2):c.1327G>A(p.Val443Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V443L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SBF2
NM_030962.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.95

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4B2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics

SBF2 links:

ENSG00000286561 (HGNC:):

ENSG00000286561 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13903177).

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.1327G>A	p.Val443Ile	missense	Exon 13 of 40	NP_112224.1
SBF2	NM_001386339.1		c.1327G>A	p.Val443Ile	missense	Exon 13 of 41	NP_001373268.1
SBF2	NM_001424318.1		c.1363G>A	p.Val455Ile	missense	Exon 14 of 41	NP_001411247.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SBF2	ENST00000256190.13	TSL:1 MANE Select	c.1327G>A	p.Val443Ile	missense	Exon 13 of 40	ENSP00000256190.8
SBF2	ENST00000533770.6	TSL:1	c.1327G>A	p.Val443Ile	missense	Exon 13 of 26	ENSP00000509247.1
SBF2	ENST00000526353.2	TSL:1	n.1477G>A		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457098

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725060

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

85830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1108318

Other (OTH)

AF:

0.00

AC:

AN:

60202

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.23

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

M_CAP

Benign

0.015

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.34

PhyloP100

3.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.66

REVEL

Benign

0.24

Sift

Benign

0.13

Sift4G

Benign

0.21

Polyphen

0.088

Vest4

0.10

MutPred

0.34

Loss of methylation at K442 (P = 0.0563)

MVP

0.78

MPC

0.14

ClinPred

0.43

GERP RS

5.3

PromoterAI

0.0031

Neutral

(source)

Varity_R

0.086

gMVP

0.19

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over