rs34775878

Positions:

• chr11-66714162-G-A

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.585C>T​(p.Asn195Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,584 control chromosomes in the GnomAD database, including 9,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (729 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8736 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.946

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=-0.37).
• BP6: Variant 11-66714162-G-A is Benign according to our data. Variant chr11-66714162-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66714162-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.946 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.585C>T	p.Asn195Asn	synonymous_variant	7/38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.585C>T	p.Asn195Asn	synonymous_variant	7/38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12163 AN: 152196 Hom.: 728 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.0814 AC: 20466 AN: 251456 Hom.: 1120 AF XY: 0.0840 AC XY: 11417 AN XY: 135914

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0694

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0438

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.103 AC: 149905 AN: 1461270 Hom.: 8736 Cov.: 33 AF XY: 0.102 AC XY: 74007 AN XY: 726964

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0452

Gnomad4 FIN exome AF: 0.0354

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0798 AC: 12158 AN: 152314 Hom.: 729 Cov.: 32 AF XY: 0.0766 AC XY: 5705 AN XY: 74486

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0968

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0456

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.101

Alfa AF: 0.107 Hom.: 501

Bravo AF: 0.0838

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

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. -

Spinocerebellar ataxia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

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	-0.37
CADD	Benign	9.0
DANN	Benign	0.86

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: rs34775878; hg19: chr11-66481633;