11-66687135-C-A

Position:

• chr11-66687135-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006946.4(SPTBN2):​c.6755G>T​(p.Arg2252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.419

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.6755G>T	p.Arg2252Leu	missense_variant	36/38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.6755G>T	p.Arg2252Leu	missense_variant	36/38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.77	.;T;.;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N;N;.;N;.
REVEL	Benign	0.12
Sift	Benign	0.23	T;T;.;T;.
Sift4G	Benign	0.19	T;T;D;T;D
Polyphen		0.027	B;B;.;.;.
Vest4		0.61
MutPred		0.69		Loss of MoRF binding (P = 0.0197);Loss of MoRF binding (P = 0.0197);.;Loss of MoRF binding (P = 0.0197);.;
MVP		0.59
MPC		0.70
ClinPred		0.58	D
GERP RS		3.4
Varity_R		0.12
gMVP		0.50

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: rs529514462; hg19: chr11-66454606;