11-66700998-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_006946.4(SPTBN2):c.3101T>C(p.Val1034Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,607,566 control chromosomes in the GnomAD database, including 11,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2418 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8930 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.199

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SPTBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004006833).
• BP6: Variant 11-66700998-A-G is Benign according to our data. Variant chr11-66700998-A-G is described in ClinVar as [Benign]. Clinvar id is 130371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66700998-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.3101T>C	p.Val1034Ala	missense_variant	17/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.3101T>C	p.Val1034Ala	missense_variant	17/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23900 AN: 152102 Hom.: 2405 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0952

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.127 AC: 30853 AN: 242912 Hom.: 2460 AF XY: 0.123 AC XY: 16287 AN XY: 132588

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.0943

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.0957

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.102 AC: 148257 AN: 1455346 Hom.: 8930 Cov.: 34 AF XY: 0.102 AC XY: 73628 AN XY: 724346

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0952

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.0882

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.157 AC: 23935 AN: 152220 Hom.: 2418 Cov.: 33 AF XY: 0.159 AC XY: 11819 AN XY: 74436

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0952

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.0928

Gnomad4 OTH AF: 0.154

Alfa AF: 0.102 Hom.: 2171

Bravo AF: 0.159

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0835 AC: 322

ESP6500AA AF: 0.261 AC: 1146

ESP6500EA AF: 0.0924 AC: 793

ExAC AF: 0.131 AC: 15840

Asia WGS AF: 0.200 AC: 694 AN: 3478

EpiCase AF: 0.0870

EpiControl AF: 0.0903

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	- -

Spinocerebellar ataxia type 5 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	12
Dann	Benign	0.28
DEOGEN2	Benign	0.064	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0095	N
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.90	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.80	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.021
MPC		0.49
ClinPred		0.0056	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.031
gMVP		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs506028; hg19: chr11-66468469; COSMIC: COSV59451964; COSMIC: COSV59451964;