rs35532855

Variant names:

• chr11-66690210-C-T
• rs35532855
• NM_006946.4:c.5639G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-66690210-C-T
• chr11-66690210-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 12/21 in silico tools predict 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:6
• Conservation: PhyloP100: 0.753
• Publications: 10 publications found

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]

SPTBN2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• autosomal recessive spinocerebellar ataxia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 305546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	NM_006946.4	MANE Select	c.5639G>A	p.Arg1880His	missense	Exon 28 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.5660G>A	p.Arg1887His	missense	Exon 26 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.5639G>A	p.Arg1880His	missense	Exon 27 of 37	NP_001424470.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.5639G>A	p.Arg1880His	missense	Exon 28 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.5639G>A	p.Arg1880His	missense	Exon 27 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.5660G>A	p.Arg1887His	missense	Exon 26 of 36	ENSP00000482000.2	A0A087WYQ1

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

GnomAD2 exomes AF: 0.0168 AC: 4135 AN: 246366 AF XY: 0.0176

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 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

African (AFR) AF: 0.00341 AC: 114 AN: 33476

American (AMR) AF: 0.0145 AC: 650 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 518 AN: 26090

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00643 AC: 554 AN: 86218

European-Finnish (FIN) AF: 0.00936 AC: 498 AN: 53208

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5764

European-Non Finnish (NFE) AF: 0.0263 AC: 29213 AN: 1111866

Other (OTH) AF: 0.0213 AC: 1284 AN: 60366

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

African (AFR) AF: 0.00414 AC: 172 AN: 41580

American (AMR) AF: 0.0189 AC: 289 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.00734 AC: 78 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0249 AC: 1694 AN: 68024

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0231 Hom.: 105

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.75
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.083
Sift	Benign	0.061	T
Sift4G	Benign	0.10	T
Polyphen		1.0	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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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