rs761263852

chr11-66704629-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_006946.4(SPTBN2):c.2647C>T(p.Arg883Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,612,006 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (2 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.92

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 Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SPTBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.27514702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.2647C>T	p.Arg883Cys	missense_variant	15/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.2647C>T	p.Arg883Cys	missense_variant	15/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151880 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000660 AC: 16 AN: 242556 Hom.: 0 AF XY: 0.0000606 AC XY: 8 AN XY: 132080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1460126 Hom.: 2 Cov.: 73 AF XY: 0.0000496 AC XY: 36 AN XY: 726242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151880 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 5 AN XY: 74168

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.2647C>T (p.R883C) alteration is located in exon 14 (coding exon 13) of the SPTBN2 gene. This alteration results from a C to T substitution at nucleotide position 2647, causing the arginine (R) at amino acid position 883 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.044	D;D;D
Sift4G	Uncertain	0.052	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.39
MVP		0.48
MPC		1.3
ClinPred		0.41	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.41

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: rs761263852; hg19: chr11-66472100; COSMIC: COSV59455487;