11-66688301-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006946.4(SPTBN2):c.6242G>A(p.Arg2081Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,594,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2081W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.58

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038062036).

BP6

Variant 11-66688301-C-T is Benign according to our data. Variant chr11-66688301-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305538.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000263 (40/152202) while in subpopulation AMR AF = 0.00131 (20/15294). AF 95% confidence interval is 0.000866. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTBN2	NM_006946.4	MANE Select	c.6242G>A	p.Arg2081Gln	missense	Exon 32 of 38	NP_008877.2
SPTBN2	NM_001411025.1		c.6263G>A	p.Arg2088Gln	missense	Exon 30 of 36	NP_001397954.1
SPTBN2	NM_001437541.1		c.6242G>A	p.Arg2081Gln	missense	Exon 31 of 37	NP_001424470.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.6242G>A	p.Arg2081Gln	missense	Exon 32 of 38	ENSP00000432568.1
SPTBN2	ENST00000309996.7	TSL:1	c.6242G>A	p.Arg2081Gln	missense	Exon 31 of 37	ENSP00000311489.2
SPTBN2	ENST00000617502.5	TSL:5	c.6263G>A	p.Arg2088Gln	missense	Exon 30 of 36	ENSP00000482000.2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000129

AC:

AN:

209976

AF XY:

0.000114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000564

GnomAD4 exome

AF:

0.000281

AC:

405

AN:

1442578

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

187

AN XY:

716174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32998

American (AMR)

AF:

0.000336

AC:

AN:

41634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

38616

South Asian (SAS)

AF:

0.00

AC:

AN:

84058

European-Finnish (FIN)

AF:

0.0000388

AC:

AN:

51568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000338

AC:

373

AN:

1102608

Other (OTH)

AF:

0.000268

AC:

AN:

59640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68040

Other (OTH)

AF:

0.00239

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000147

Hom.:

Bravo

AF:

0.000397

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000994

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal dominant cerebellar ataxia (1)

Inborn genetic diseases (1)

Spinocerebellar ataxia type 5;C4706415:Autosomal recessive spinocerebellar ataxia 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.091

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.018

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.77

PhyloP100

1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.30

REVEL

Benign

0.035

Sift

Benign

0.22

Sift4G

Benign

0.53

Polyphen

0.0090

Vest4

0.12

MVP

0.50

MPC

0.47

ClinPred

0.041

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.023

gMVP

0.070

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over