rs120074138

chr11-9832290-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_030962.4(SBF2):c.3586C>T(p.Arg1196Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SBF2 NM_030962.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-9832290-G-A is Pathogenic according to our data. Variant chr11-9832290-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2911.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-9832290-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBF2	NM_030962.4	c.3586C>T	p.Arg1196Ter	stop_gained	27/40	ENST00000256190.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBF2	ENST00000256190.13	c.3586C>T	p.Arg1196Ter	stop_gained	27/40	1	NM_030962.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2003

- -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SBF2 are known to be pathogenic (PMID: 25873783, 12687498). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12687498). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2911). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1196*) in the SBF2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.92
GERP RS		5.8

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

Other links and lift over

dbSNP: rs120074138; hg19: chr11-9853837;