11-9845712-A-C

Variant names:

• chr11-9845712-A-C
• rs778766567
• NM_030962.4:c.2963T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030962.4(SBF2):​c.2963T>G​(p.Val988Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SBF2 NM_030962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.93
• Publications: 0 publications found

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

ENSG00000255476 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	NM_030962.4	MANE Select	c.2963T>G	p.Val988Gly	missense	Exon 24 of 40	NP_112224.1
	SBF2	NM_001386339.1		c.2963T>G	p.Val988Gly	missense	Exon 24 of 41	NP_001373268.1
	SBF2	NM_001424318.1		c.2999T>G	p.Val1000Gly	missense	Exon 25 of 41	NP_001411247.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	ENST00000256190.13	TSL:1 MANE Select	c.2963T>G	p.Val988Gly	missense	Exon 24 of 40	ENSP00000256190.8
	SBF2	ENST00000533770.6	TSL:1	c.2963T>G	p.Val988Gly	missense	Exon 24 of 26	ENSP00000509247.1
	ENSG00000255476	ENST00000533659.1	TSL:1	n.134+6436A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251284 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1

Sep 23, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SBF2-related disease. This variant is present in population databases (rs778766567, ExAC 0.003%). This sequence change replaces valine with glycine at codon 988 of the SBF2 protein (p.Val988Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.34		Gain of disorder (P = 0.0437)
MVP		0.96
MPC		0.83
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.86
Mutation Taster		=31/69	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

Other links and lift over

dbSNP: rs778766567; hg19: chr11-9867259;