rs141330687

Variant names:

• chr11-9856498-C-T
• rs141330687
• NM_030962.4:c.2323G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030962.4(SBF2):​c.2323G>A​(p.Gly775Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,614,170 control chromosomes in the GnomAD database, including 18 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. G775G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: SBF2 NM_030962.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:16
• Conservation: PhyloP100: 3.29
• Publications: 11 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Ambry Genetics, G2P, Orphanet

ENSG00000255476 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010010332).
• BP6: Variant 11-9856498-C-T is Benign according to our data. Variant chr11-9856498-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194989.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00273 (416/152314) while in subpopulation NFE AF = 0.0047 (320/68024). AF 95% confidence interval is 0.00428. There are 1 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	NM_030962.4	MANE Select	c.2323G>A	p.Gly775Ser	missense	Exon 19 of 40	NP_112224.1	Q86WG5-1
	SBF2	NM_001386339.1		c.2323G>A	p.Gly775Ser	missense	Exon 19 of 41	NP_001373268.1	A0A8I5KQ02
	SBF2	NM_001424318.1		c.2359G>A	p.Gly787Ser	missense	Exon 20 of 41	NP_001411247.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	ENST00000256190.13	TSL:1 MANE Select	c.2323G>A	p.Gly775Ser	missense	Exon 19 of 40	ENSP00000256190.8	Q86WG5-1
	SBF2	ENST00000533770.6	TSL:1	c.2323G>A	p.Gly775Ser	missense	Exon 19 of 26	ENSP00000509247.1	Q86WG5-3
	ENSG00000255476	ENST00000533659.1	TSL:1	n.134+17222C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00320 AC: 805 AN: 251432 AF XY: 0.00326

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00376 AC: 5491 AN: 1461856 Hom.: 17 Cov.: 33 AF XY: 0.00378 AC XY: 2749 AN XY: 727228

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.00400 AC: 179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00311 AC: 268 AN: 86250

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53420

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5758

European-Non Finnish (NFE) AF: 0.00427 AC: 4749 AN: 1111996

Other (OTH) AF: 0.00275 AC: 166 AN: 60394

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74490

African (AFR) AF: 0.000698 AC: 29 AN: 41564

American (AMR) AF: 0.00222 AC: 34 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00470 AC: 320 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00386 Hom.: 6

Bravo AF: 0.00258

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00322 AC: 391

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	2	Charcot-Marie-Tooth disease type 4B2 (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SBF2-related disorder (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.36
Sift	Benign	0.36	T
Sift4G	Benign	0.36	T
Polyphen		0.76	P
Vest4		0.47
MVP		0.90
MPC		0.19
ClinPred		0.020	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.35
Mutation Taster		=80/20	disease causing (ClinVar)

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: rs141330687; hg19: chr11-9878045; COSMIC: COSV56304153;