chr11-66704803-T-G

Variant names:

• chr11-66704803-T-G
• rs4930388
• NM_006946.4:c.2473A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006946.4(SPTBN2):​c.2473A>C​(p.Ser825Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S825G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 36)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 25 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):

• autosomal recessive spinocerebellar ataxia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• spinocerebellar ataxia type 5

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12940684).

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.2473A>C	p.Ser825Arg	missense	Exon 15 of 38	NP_008877.2
	SPTBN2	NM_001411025.1		c.2494A>C	p.Ser832Arg	missense	Exon 13 of 36	NP_001397954.1
	SPTBN2	NM_001437541.1		c.2473A>C	p.Ser825Arg	missense	Exon 14 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.2473A>C	p.Ser825Arg	missense	Exon 15 of 38	ENSP00000432568.1
	SPTBN2	ENST00000309996.7	TSL:1	c.2473A>C	p.Ser825Arg	missense	Exon 14 of 37	ENSP00000311489.2
	SPTBN2	ENST00000617502.5	TSL:5	c.2494A>C	p.Ser832Arg	missense	Exon 13 of 36	ENSP00000482000.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 106

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N
PhyloP100		2.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.14
Sift	Benign	0.49	T
Sift4G	Benign	0.51	T
Polyphen		0.044	B
Vest4		0.15
MutPred		0.30		Loss of glycosylation at S825 (P = 0.0085)
MVP		0.36
MPC		0.47
ClinPred		0.61	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.36
Mutation Taster		=93/7	polymorphism

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: rs4930388; hg19: chr11-66472274;