rs372553453

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_006946.4(SPTBN2):c.3707G>A(p.Arg1236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.39

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19145131).

BP6

Variant 11-66699475-C-T is Benign according to our data. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66699475-C-T is described in CliVar as Likely_benign. Clinvar id is 586478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.3707G>A	p.Arg1236His	missense_variant	Exon 18 of 38	ENST00000533211.6	NP_008877.2	O15020-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 link	c.3707G>A	p.Arg1236His	missense_variant	Exon 18 of 38	5	NM_006946.4	ENSP00000432568.1		O15020-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251478

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112006

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000965

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 26, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

0.072

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.70

.;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.0

M;M;M

PhyloP100

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.043

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.28

MVP

0.51

MPC

0.67

ClinPred

0.097

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.22

Mutation Taster

=61/39

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

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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