11-66690210-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006946.4(SPTBN2):c.5639G>A(p.Arg1880His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,734 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1880C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (19 hom., cov: 32)
  • Exomes 𝑓: 0.023 (441 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.753

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=0.0050126016).
• BP6: Variant 11-66690210-C-T is Benign according to our data. Variant chr11-66690210-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 305546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66690210-C-T is described in Lovd as [Benign]. Variant chr11-66690210-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0159 (2419/152360) while in subpopulation NFE AF= 0.0249 (1694/68024). AF 95% confidence interval is 0.0239. There are 19 homozygotes in gnomad4. There are 1136 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.5639G>A	p.Arg1880His	missense_variant	28/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.5639G>A	p.Arg1880His	missense_variant	28/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2425 AN: 152242 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0168 AC: 4135 AN: 246366 Hom.: 46 AF XY: 0.0176 AC XY: 2348 AN XY: 133632

Gnomad AFR exome AF: 0.00510

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00590

Gnomad FIN exome AF: 0.00928

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0226 AC: 32975 AN: 1461374 Hom.: 441 Cov.: 32 AF XY: 0.0223 AC XY: 16196 AN XY: 727022

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00643

Gnomad4 FIN exome AF: 0.00936

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0159 AC: 2419 AN: 152360 Hom.: 19 Cov.: 32 AF XY: 0.0152 AC XY: 1136 AN XY: 74508

Gnomad4 AFR AF: 0.00414

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00734

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.0240 Hom.: 84

Bravo AF: 0.0166

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0170 AC: 2068

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.083
Sift	Benign	0.061	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.13
MPC		0.52
ClinPred		0.030	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.20

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: rs35532855; hg19: chr11-66457681; COSMIC: COSV99047487; COSMIC: COSV99047487;