rs797046005

Positions:

• chr11-66710612-T-A
• chr11-66710612-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006946.4(SPTBN2):​c.1043A>T​(p.Asn348Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N348D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.85

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-66710613-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436854.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SPTBN2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 11-66710612-T-A is Pathogenic according to our data. Variant chr11-66710612-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212299.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.1043A>T	p.Asn348Ile	missense_variant	10/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.1043A>T	p.Asn348Ile	missense_variant	10/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.8	D;D;.;D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;.;D;.
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.81
MutPred		0.57		Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);Loss of disorder (P = 0.0255);
MVP		0.76
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.80

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: rs797046005; hg19: chr11-66478083;