rs763770499

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_006946.4(SPTBN2):c.5060G>A(p.Arg1687Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,605,486 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1687W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant where missense usually causes diseases, SPTBN2

BP4

Computational evidence support a benign effect (MetaRNN=0.24226561).

BP6

Variant 11-66692666-C-T is Benign according to our data. Variant chr11-66692666-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448509.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4 linkuse as main transcript	c.5060G>A	p.Arg1687Gln	missense_variant	26/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6 linkuse as main transcript	c.5060G>A	p.Arg1687Gln	missense_variant	26/38	5	NM_006946.4	P1	O15020-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000782

AC:

AN:

242872

Hom.:

AF XY:

0.0000831

AC XY:

AN XY:

132338

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1453260

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

723442

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 08, 2017

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.20

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.0055

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

0.97

D;D;.

Vest4

0.33

MVP

0.62

MPC

0.52

ClinPred

0.40

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.45

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over