rs147766428

chr11-66721149-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS1

The NM_006946.4(SPTBN2):c.92C>T(p.Ser31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,614,140 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S31P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (4 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.18

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 276) in uniprot entity SPTN2_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_006946.4
• PP2: Missense variant where missense usually causes diseases, SPTBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.029143512).
• BP6: Variant 11-66721149-G-A is Benign according to our data. Variant chr11-66721149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448526.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000545 (83/152246) while in subpopulation NFE AF= 0.001 (68/68026). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.92C>T	p.Ser31Leu	missense_variant	3/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.92C>T	p.Ser31Leu	missense_variant	3/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000521 AC: 131 AN: 251472 Hom.: 0 AF XY: 0.000574 AC XY: 78 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000951 AC: 1390 AN: 1461894 Hom.: 4 Cov.: 31 AF XY: 0.000898 AC XY: 653 AN XY: 727248

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74420

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000576 AC: 70

EpiCase AF: 0.00115

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 31, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2022

Unlikely to be causative of SPTBN2-related spinocerebellar ataxia (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 5;C4706415:Autosomal recessive spinocerebellar ataxia 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 27, 2021

ACMG classification criteria: BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.029	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;.;N;.;N
REVEL	Benign	0.071
Sift	Benign	0.20	T;T;.;T;.;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.013	B;B;.;.;.;.
Vest4		0.20
MVP		0.43
MPC		0.71
ClinPred		0.015	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.28

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: rs147766428; hg19: chr11-66488620;