rs777790247

Positions:

chr11-66701155-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6

The NM_006946.4(SPTBN2):c.2944G>A(p.Glu982Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.13

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 Uncertain_significance. Variant got 0 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN2. . Gene score misZ 2.6349 (greater than the threshold 3.09). Trascript score misZ 4.499 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive spinocerebellar ataxia 14, spinocerebellar ataxia type 5.

BP6

Variant 11-66701155-C-T is Benign according to our data. Variant chr11-66701155-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448491.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4 linkuse as main transcript	c.2944G>A	p.Glu982Lys	missense_variant	17/38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 linkuse as main transcript	c.2944G>A	p.Glu982Lys	missense_variant	17/38	5	NM_006946.4	ENSP00000432568	P1	O15020-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249146

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135338

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460808

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000150

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The c.2944G>A (p.E982K) alteration is located in exon 16 (coding exon 15) of the SPTBN2 gene. This alteration results from a G to A substitution at nucleotide position 2944, causing the glutamic acid (E) at amino acid position 982 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 12, 2017

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.5

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Benign

0.18

Sift

Benign

0.035

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.91

P;P;.

Vest4

0.80

MutPred

0.55

Gain of MoRF binding (P = 0.0016);Gain of MoRF binding (P = 0.0016);Gain of MoRF binding (P = 0.0016);

MVP

0.73

MPC

1.3

ClinPred

0.72

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.53

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