rs189911105
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_030962.4(SBF2):āc.4666T>Cā(p.Phe1556Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,585,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.000017 ( 0 hom. )
Consequence
SBF2
NM_030962.4 missense
NM_030962.4 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 8.95
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-AS1 (HGNC:27438): (SBF2 antisense RNA 1)
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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;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SBF2 | NM_030962.4 | c.4666T>C | p.Phe1556Leu | missense_variant | 34/40 | ENST00000256190.13 | |
SBF2-AS1 | NR_036485.1 | n.212-17260A>G | intron_variant, non_coding_transcript_variant | ||||
LOC105369149 | XR_007062587.1 | n.356-281A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SBF2 | ENST00000256190.13 | c.4666T>C | p.Phe1556Leu | missense_variant | 34/40 | 1 | NM_030962.4 | P3 | |
SBF2-AS1 | ENST00000663578.1 | n.237-17260A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247664Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133636
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GnomAD4 exome AF: 0.0000167 AC: 24AN: 1433576Hom.: 0 Cov.: 27 AF XY: 0.0000224 AC XY: 16AN XY: 714228
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GnomAD4 genome AF: 0.00000656 AC: 1AN: 152368Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74518
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 07, 2018 | The SBF2 c.4666T>C; p.Phe1556Leu variant (rs189911105), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 4 out of 242,768 chromosomes). The phenylalanine at position 1556 is moderately conserved, considering 11 species, and computational analyses of the effects of the p.Phe1556Leu variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Phe1556Leu variant cannot be determined with certainty. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1556 of the SBF2 protein (p.Phe1556Leu). This variant is present in population databases (rs189911105, gnomAD 0.003%). 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: 578429). 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: "Deleterious"; PolyPhen-2: "Benign"; 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of sheet (P = 0.0477);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at