11-66715248-C-T

Variant names:

• chr11-66715248-C-T
• rs1554989084
• NM_006946.4:c.457G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006946.4(SPTBN2):​c.457G>A​(p.Val153Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 4.87

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.

• PM1: In a region_of_interest Actin-binding (size 276) in uniprot entity SPTN2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006946.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12997872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.457G>A	p.Val153Ile	missense_variant	Exon 5 of 38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.457G>A	p.Val153Ile	missense_variant	Exon 5 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.40	T;T;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	.;D;.;D;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;N;.;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.78	N;N;.;N;.
REVEL	Benign	0.091
Sift	Benign	1.0	T;T;.;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.033	B;B;.;.;.
Vest4		0.21
MutPred		0.60		Gain of catalytic residue at L158 (P = 0.1381);Gain of catalytic residue at L158 (P = 0.1381);Gain of catalytic residue at L158 (P = 0.1381);Gain of catalytic residue at L158 (P = 0.1381);Gain of catalytic residue at L158 (P = 0.1381);
MVP		0.32
MPC		0.66
ClinPred		0.80	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1554989084; hg19: chr11-66482719;