rs397514749

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_006946.4(SPTBN2):c.1438C>T(p.Arg480Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R480G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 6.65

Publications

21 publications found

Variant links:

COSMIC-nc: COSV59457011

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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 11-66707731-G-A is Pathogenic according to our data. Variant chr11-66707731-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64368.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.1438C>T	p.Arg480Trp	missense_variant	Exon 13 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.1438C>T	p.Arg480Trp	missense_variant	Exon 13 of 38	5	NM_006946.4	ENSP00000432568.1		O15020-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

243820

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722732

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39592

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110082

Other (OTH)

AF:

0.00

AC:

AN:

60216

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 5

Pathogenic:5Uncertain:1

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with autosomal dominant spinocerebellar ataxia 5 (MIM#600224; PMID: 31617442, 31066025). Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spinocerebellar ataxia 14 (MIM#615386; PMID: 23236289, 31617442, 31066025). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous missense and in frame deletion variants in SPTBN2 have been associated with autosomal dominant spinocerebellar ataxia type 5 (MIM#600224; PMID: 31617442, 31066025). Biallelic loss of function variants have been associated with autosomal recessive spinocerebellar ataxia 14 (MIM#615386; PMID: 23236289, 31617442, 31066025). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated spectrin repeat domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, as well as a VUS entry. In addition, this variant has been observed in multiple heterozygous individuals with congenital spinocerebellar ataxia, five of which were confirmed to be de novo (ClinVar, DECIPHER, PMID: 33318253, 29795474, 22914369, 25981959). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Dec 23, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29196973, 25142508, 22914369, 31066025, 25981959, 31617442, 30898343, 29795474, 28636205, 31721007, 30167849, 23838597, 29795473, 33084218, 31785789, 33318253, 26821241) -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 480 of the SPTBN2 protein (p.Arg480Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 22914369, 25981959, 33318253). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 64368). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPTBN2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPTBN2 function (PMID: 25981959). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 12, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1438C>T (p.R480W) alteration is located in exon 12 (coding exon 11) of the SPTBN2 gene. This alteration results from a C to T substitution at nucleotide position 1438, causing the arginine (R) at amino acid position 480 to be replaced by a tryptophan (W). The SPTBN2 c.1438C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant SPTBN2-related spinocerebellar ataxia (Parolin Schnekenberg, 2015; Nuovo, 2018; Zonta, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;.;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

.;D;.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Uncertain

0.056

MutationAssessor

Pathogenic

4.2

H;H;.;H;.

PhyloP100

6.7

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.5

D;D;.;D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.95

MutPred

0.81

Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);

MVP

0.83

MPC

1.9

ClinPred

1.0

GERP RS

3.5

Varity_R

0.87

gMVP

0.92

Mutation Taster

=11/89

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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