rs639938

chr11-66693056-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006946.4(SPTBN2):c.4899G>A(p.Leu1633=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,613,912 control chromosomes in the GnomAD database, including 3,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (379 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2824 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.33

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-66693056-C-T is Benign according to our data. Variant chr11-66693056-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 305553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66693056-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.4899G>A	p.Leu1633=	synonymous_variant	25/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.4899G>A	p.Leu1633=	synonymous_variant	25/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9499 AN: 152170 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0555

GnomAD3 exomes AF: 0.0678 AC: 17031 AN: 251096 Hom.: 760 AF XY: 0.0668 AC XY: 9072 AN XY: 135762

Gnomad AFR exome AF: 0.0521

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.0696

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0567

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0561 AC: 82046 AN: 1461624 Hom.: 2824 Cov.: 33 AF XY: 0.0564 AC XY: 41025 AN XY: 727122

Gnomad4 AFR exome AF: 0.0521

Gnomad4 AMR exome AF: 0.0574

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0664

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.0507

Gnomad4 OTH exome AF: 0.0566

GnomAD4 genome AF: 0.0625 AC: 9522 AN: 152288 Hom.: 379 Cov.: 32 AF XY: 0.0664 AC XY: 4946 AN XY: 74460

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.0599

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0751

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.0542

Gnomad4 OTH AF: 0.0535

Alfa AF: 0.0500 Hom.: 341

Bravo AF: 0.0539

Asia WGS AF: 0.125 AC: 433 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

SPTBN2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

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

Autosomal dominant cerebellar ataxia Benign:1

Likely 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
BayesDel_noAF	Benign	-0.35
Cadd	Benign	6.2
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs639938; hg19: chr11-66460527; COSMIC: COSV59447137; COSMIC: COSV59447137;