11-66700998-A-G

Position:

chr11-66700998-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_006946.4(SPTBN2):c.3101T>C(p.Val1034Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,607,566 control chromosomes in the GnomAD database, including 11,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2418 hom., cov: 33)

Exomes 𝑓: 0.10 ( 8930 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.199

Variant links:

Genes affected

SPTBN2 (HGNC:11276): (spectrin beta, non-erythrocytic 2) Spectrins are principle components of a cell's membrane-cytoskeleton and are composed of two alpha and two beta spectrin subunits. The protein encoded by this gene (SPTBN2), is called spectrin beta non-erythrocytic 2 or beta-III spectrin. It is related to, but distinct from, the beta-II spectrin gene which is also known as spectrin beta non-erythrocytic 1 (SPTBN1). SPTBN2 regulates the glutamate signaling pathway by stabilizing the glutamate transporter EAAT4 at the surface of the plasma membrane. Mutations in this gene cause a form of spinocerebellar ataxia, SCA5, that is characterized by neurodegeneration, progressive locomotor incoordination, dysarthria, and uncoordinated eye movements. [provided by RefSeq, Dec 2009]

SPTBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN2. . Gene score misZ 2.6349 (greater than the threshold 3.09). Trascript score misZ 4.499 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive spinocerebellar ataxia 14, spinocerebellar ataxia type 5.

BP4

Computational evidence support a benign effect (MetaRNN=0.004006833).

BP6

Variant 11-66700998-A-G is Benign according to our data. Variant chr11-66700998-A-G is described in ClinVar as [Benign]. Clinvar id is 130371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66700998-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4 linkuse as main transcript	c.3101T>C	p.Val1034Ala	missense_variant	17/38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 linkuse as main transcript	c.3101T>C	p.Val1034Ala	missense_variant	17/38	5	NM_006946.4	ENSP00000432568	P1	O15020-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23900

AN:

152102

Hom.:

2405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.0952

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.171

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0928

Gnomad OTH

AF:

0.158

GnomAD3 exomes

AF:

0.127

AC:

30853

AN:

242912

Hom.:

2460

AF XY:

0.123

AC XY:

16287

AN XY:

132588

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.0997

Gnomad ASJ exome

AF:

0.0943

Gnomad EAS exome

AF:

0.258

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.0957

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.102

AC:

148257

AN:

1455346

Hom.:

8930

Cov.:

AF XY:

0.102

AC XY:

73628

AN XY:

724346

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.0952

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.107

Gnomad4 FIN exome

AF:

0.157

Gnomad4 NFE exome

AF:

0.0882

Gnomad4 OTH exome

AF:

0.115

GnomAD4 genome

AF:

0.157

AC:

23935

AN:

152220

Hom.:

2418

Cov.:

AF XY:

0.159

AC XY:

11819

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.0952

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.171

Gnomad4 NFE

AF:

0.0928

Gnomad4 OTH

AF:

0.154

Alfa

AF:

0.102

Hom.:

2171

Bravo

AF:

0.159

TwinsUK

AF:

0.0874

AC:

324

ALSPAC

AF:

0.0835

AC:

322

ESP6500AA

AF:

0.261

AC:

1146

ESP6500EA

AF:

0.0924

AC:

793

ExAC

AF:

0.131

AC:

15840

Asia WGS

AF:

0.200

AC:

694

AN:

3478

EpiCase

AF:

0.0870

EpiControl

AF:

0.0903

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Spinocerebellar ataxia type 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.28

DEOGEN2

Benign

0.064

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.15

.;T;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.90

N;N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

1.3

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.80

T;T;T

Sift4G

Benign

0.76

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.021

MPC

0.49

ClinPred

0.0056

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.031

gMVP

0.078

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over