chr11-66711028-G-C

Variant names:

• chr11-66711028-G-C
• rs139240091
• NM_006946.4:c.774C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_006946.4(SPTBN2):​c.774C>G​(p.Asp258Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN2 NM_006946.4 missense, splice_region
• Scores: Splicing: ADA: 0.000005629
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.792

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 Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.774C>G	p.Asp258Glu	missense_variant, splice_region_variant	Exon 9 of 38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.774C>G	p.Asp258Glu	missense_variant, splice_region_variant	Exon 9 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 13, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 10, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D258E variant in the SPTBN2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D258E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D258E variant is a conservative amino acid substitution, which occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret D258E as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;.;.;.
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	.;D;.;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.5	M;M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;D;.;D;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.72
MutPred		0.78		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.81
MPC		1.8
ClinPred		0.97	D
GERP RS		0.38
Varity_R		0.88
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000056
dbscSNV1_RF	Benign	0.028
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: rs139240091; hg19: chr11-66478499;