rs749281906

Positions:

• chr11-66704781-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_006946.4(SPTBN2):​c.2495G>A​(p.Arg832Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,603,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

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 -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN2. . Gene score misZ 2.6349 (greater than the threshold 3.09). Trascript score misZ 4.499 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive spinocerebellar ataxia 14, spinocerebellar ataxia type 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0139526725).
• BP6: Variant 11-66704781-C-T is Benign according to our data. Variant chr11-66704781-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.2495G>A	p.Arg832Gln	missense_variant	15/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.2495G>A	p.Arg832Gln	missense_variant	15/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152242 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000823 AC: 19 AN: 230898 Hom.: 0 AF XY: 0.0000784 AC XY: 10 AN XY: 127524

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.0000887

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1451750 Hom.: 0 Cov.: 75 AF XY: 0.0000249 AC XY: 18 AN XY: 722276

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74384

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.0000751 AC: 9

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.50
DEOGEN2	Benign	0.067	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.54	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.75	T;T;T
Sift4G	Benign	0.89	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.062
MutPred		0.39		Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);
MVP		0.22
MPC		0.47
ClinPred		0.00077	T
GERP RS		-0.58
Varity_R		0.040
gMVP		0.076

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: rs749281906; hg19: chr11-66472252; COSMIC: COSV59449067;