NM_006946.4:c.3101T>C

Variant names:

• chr11-66700998-A-G
• rs506028
• NM_006946.4:c.3101T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1034M) has been classified as Uncertain significance.

• 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:8
• Conservation: PhyloP100: -0.199
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 130371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	NM_006946.4	MANE Select	c.3101T>C	p.Val1034Ala	missense	Exon 17 of 38	NP_008877.2
	SPTBN2	NM_001411025.1		c.3122T>C	p.Val1041Ala	missense	Exon 15 of 36	NP_001397954.1
	SPTBN2	NM_001437541.1		c.3101T>C	p.Val1034Ala	missense	Exon 16 of 37	NP_001424470.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.3101T>C	p.Val1034Ala	missense	Exon 17 of 38	ENSP00000432568.1
	SPTBN2	ENST00000309996.7	TSL:1	c.3101T>C	p.Val1034Ala	missense	Exon 16 of 37	ENSP00000311489.2
	SPTBN2	ENST00000617502.5	TSL:5	c.3122T>C	p.Val1041Ala	missense	Exon 15 of 36	ENSP00000482000.2

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

GnomAD2 exomes AF: 0.127 AC: 30853 AN: 242912 AF XY: 0.123

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 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

African (AFR) AF: 0.278 AC: 9302 AN: 33470

American (AMR) AF: 0.102 AC: 4557 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 2485 AN: 26110

East Asian (EAS) AF: 0.246 AC: 9773 AN: 39692

South Asian (SAS) AF: 0.107 AC: 9245 AN: 86242

European-Finnish (FIN) AF: 0.157 AC: 7407 AN: 47224

Middle Eastern (MID) AF: 0.0834 AC: 480 AN: 5754

European-Non Finnish (NFE) AF: 0.0882 AC: 98056 AN: 1111810

Other (OTH) AF: 0.115 AC: 6952 AN: 60338

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

African (AFR) AF: 0.274 AC: 11371 AN: 41524

American (AMR) AF: 0.122 AC: 1862 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 330 AN: 3468

East Asian (EAS) AF: 0.257 AC: 1330 AN: 5170

South Asian (SAS) AF: 0.114 AC: 549 AN: 4826

European-Finnish (FIN) AF: 0.171 AC: 1812 AN: 10614

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6313 AN: 68006

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.108 Hom.: 3512

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Spinocerebellar ataxia type 5 Benign:2

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal dominant cerebellar ataxia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.20
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.12
Sift	Benign	0.80	T
Sift4G	Benign	0.76	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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