11-66700998-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1034M) has been classified as Uncertain significance.

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

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive spinocerebellar ataxia 14
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
spinocerebellar ataxia type 5
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P

SPTBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 130371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.3101T>C	p.Val1034Ala	missense_variant	Exon 17 of 38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 link	c.3101T>C	p.Val1034Ala	missense_variant	Exon 17 of 38	5	NM_006946.4	ENSP00000432568.1

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

GnomAD2 exomes

AF:

0.127

AC:

30853

AN:

242912

AF XY:

0.123

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 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

African (AFR)

AF:

0.278

AC:

9302

AN:

33470

American (AMR)

AF:

0.102

AC:

4557

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

2485

AN:

26110

East Asian (EAS)

AF:

0.246

AC:

9773

AN:

39692

South Asian (SAS)

AF:

0.107

AC:

9245

AN:

86242

European-Finnish (FIN)

AF:

0.157

AC:

7407

AN:

47224

Middle Eastern (MID)

AF:

0.0834

AC:

480

AN:

5754

European-Non Finnish (NFE)

AF:

0.0882

AC:

98056

AN:

1111810

Other (OTH)

AF:

0.115

AC:

6952

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

10049

20099

30148

40198

50247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3760

7520

11280

15040

18800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.157

AC:

23935

AN:

152220

Hom.:

2418

Cov.:

AF XY:

0.159

AC XY:

11819

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.274

AC:

11371

AN:

41524

American (AMR)

AF:

0.122

AC:

1862

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

330

AN:

3468

East Asian (EAS)

AF:

0.257

AC:

1330

AN:

5170

South Asian (SAS)

AF:

0.114

AC:

549

AN:

4826

European-Finnish (FIN)

AF:

0.171

AC:

1812

AN:

10614

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0928

AC:

6313

AN:

68006

Other (OTH)

AF:

0.154

AC:

326

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1009

2018

3028

4037

5046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

3512

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

Oct 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Autosomal dominant cerebellar ataxia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

0.0

.;T;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.90

N;N;N

PhyloP100

-0.20

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

Vest4

0.021

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over