11-66715248-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_006946.4(SPTBN2):​c.457G>C​(p.Val153Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 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=0.389364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.457G>C	p.Val153Leu	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>C	p.Val153Leu	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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.;.;.
Eigen	Benign	0.0086
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D;.;D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;N;.;N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.0	N;N;.;N;.
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;D;.;D;.
Sift4G	Uncertain	0.037	D;D;T;D;T
Polyphen		0.62	P;P;.;.;.
Vest4		0.58
MutPred		0.65		Loss of MoRF binding (P = 0.1844);Loss of MoRF binding (P = 0.1844);Loss of MoRF binding (P = 0.1844);Loss of MoRF binding (P = 0.1844);Loss of MoRF binding (P = 0.1844);
MVP		0.48
MPC		0.94
ClinPred		0.89	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.60

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: rs1554989084; hg19: chr11-66482719;