chr11-9845619-T-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_030962.4(SBF2):​c.3056A>T​(p.Gln1019Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1019Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 1 hom. )

Consequence

SBF2
NM_030962.4 missense

Scores

2
4
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.66

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06647834).
BP6
Variant 11-9845619-T-A is Benign according to our data. Variant chr11-9845619-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448239.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000118 (18/152344) while in subpopulation EAS AF = 0.00347 (18/5190). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SBF2NM_030962.4 linkc.3056A>T p.Gln1019Leu missense_variant Exon 24 of 40 ENST00000256190.13 NP_112224.1 Q86WG5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SBF2ENST00000256190.13 linkc.3056A>T p.Gln1019Leu missense_variant Exon 24 of 40 1 NM_030962.4 ENSP00000256190.8 Q86WG5-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00346
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:
0.000322
AC:
81
AN:
251300
AF XY:
0.000309
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00435
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000855
AC:
125
AN:
1461666
Hom.:
1
Cov.:
31
AF XY:
0.0000756
AC XY:
55
AN XY:
727138
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00285
AC:
113
AN:
39684
South Asian (SAS)
AF:
0.0000580
AC:
5
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111826
Other (OTH)
AF:
0.000116
AC:
7
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
8
16
25
33
41
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.000118
AC:
18
AN:
152344
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74506
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41588
American (AMR)
AF:
0.00
AC:
0
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00347
AC:
18
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.522
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000113
Hom.:
0
Bravo
AF:
0.000174
ExAC
AF:
0.000305
AC:
37
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 28, 2017
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Aug 08, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported previously as a variant of uncertain significance in patients with Charcot-Marie-Tooth disease; however, no further information was provided (PMID: 34255403); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 38439105, 34255403) -

Inborn genetic diseases Benign:1
Jul 30, 2020
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SBF2-related disorder Benign:1
Oct 26, 2020
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 4 Benign:1
Jan 10, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.048
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.066
T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
1.4
L
PhyloP100
7.7
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.53
Sift
Benign
0.81
T
Sift4G
Benign
0.81
T
Polyphen
0.026
B
Vest4
0.89
MVP
0.89
MPC
0.18
ClinPred
0.19
T
GERP RS
5.9
Varity_R
0.30
gMVP
0.58
Mutation Taster
=38/62
disease causing

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

Other links and lift over

dbSNP: rs201964421; hg19: chr11-9867166; API