rs148154681

Positions:

chr11-66714157-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1PP2BP4_ModerateBP6_Very_StrongBS1

The NM_006946.4(SPTBN2):c.590A>G(p.Asn197Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,212 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 Benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.97

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 Benign. Variant got -11 ACMG points.

PM1

In a region_of_interest Actin-binding (size 276) in uniprot entity SPTN2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006946.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2579678).

BP6

Variant 11-66714157-T-C is Benign according to our data. Variant chr11-66714157-T-C is described in ClinVar as [Benign]. Clinvar id is 448518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000532 (81/152346) while in subpopulation AFR AF= 0.00185 (77/41572). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4 linkuse as main transcript	c.590A>G	p.Asn197Ser	missense_variant	7/38	ENST00000533211.6	NP_008877.2	O15020-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 linkuse as main transcript	c.590A>G	p.Asn197Ser	missense_variant	7/38	5	NM_006946.4	ENSP00000432568.1		O15020-1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251470

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000532

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.000691

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SPTBN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 23, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;D;D

M_CAP

Benign

0.070

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.0

M;M;.;M;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.4

D;D;.;D;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.014

D;D;.;D;.

Sift4G

Uncertain

0.0090

D;D;T;D;T

Polyphen

1.0

D;D;.;.;.

Vest4

0.82

MVP

0.85

MPC

1.6

ClinPred

0.094

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.37

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