11-66690210-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006946.4(SPTBN2):c.5639G>A(p.Arg1880His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,734 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1880C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 19 hom., cov: 32)

Exomes 𝑓: 0.023 ( 441 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.753

Publications

10 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=0.0050126016).

BP6

Variant 11-66690210-C-T is Benign according to our data. Variant chr11-66690210-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0159 (2419/152360) while in subpopulation NFE AF = 0.0249 (1694/68024). AF 95% confidence interval is 0.0239. There are 19 homozygotes in GnomAd4. There are 1136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.5639G>A	p.Arg1880His	missense_variant	Exon 28 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.5639G>A	p.Arg1880His	missense_variant	Exon 28 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2425

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0249

Gnomad OTH

AF:

0.0277

GnomAD2 exomes

AF:

0.0168

AC:

4135

AN:

246366

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00510

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00928

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0226

AC:

32975

AN:

1461374

Hom.:

441

Cov.:

AF XY:

0.0223

AC XY:

16196

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.00341

AC:

114

AN:

33476

American (AMR)

AF:

0.0145

AC:

650

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

518

AN:

26090

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00643

AC:

554

AN:

86218

European-Finnish (FIN)

AF:

0.00936

AC:

498

AN:

53208

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5764

European-Non Finnish (NFE)

AF:

0.0263

AC:

29213

AN:

1111866

Other (OTH)

AF:

0.0213

AC:

1284

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2147

4294

6441

8588

10735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1058

2116

3174

4232

5290

<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:

0.0159

AC:

2419

AN:

152360

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1136

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41580

American (AMR)

AF:

0.0189

AC:

289

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00850

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00734

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0249

AC:

1694

AN:

68024

Other (OTH)

AF:

0.0269

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

131

262

394

525

656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0231

Hom.:

105

Bravo

AF:

0.0166

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.00478

AC:

ESP6500EA

AF:

0.0255

AC:

219

ExAC

AF:

0.0170

AC:

2068

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal dominant cerebellar ataxia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.30

.;T;T

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

M;M;M

PhyloP100

0.75

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.083

Sift

Benign

0.061

T;T;T

Sift4G

Benign

0.10

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.13

MPC

0.52

ClinPred

0.030

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.20

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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