Genetic Variant NM_006946.4:c.5340C>G (chr11-66691509-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006946.4(SPTBN2):c.5340C>G(p.Asn1780Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1780S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.113

Publications

13 publications found

Variant links:

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]

SPTBN2 Gene-Disease associations (from GenCC):

autosomal recessive spinocerebellar ataxia 14
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
spinocerebellar ataxia type 5
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P

SPTBN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTBN2	NM_006946.4	MANE Select	c.5340C>G	p.Asn1780Lys	missense	Exon 27 of 38	NP_008877.2
SPTBN2	NM_001411025.1		c.5361C>G	p.Asn1787Lys	missense	Exon 25 of 36	NP_001397954.1
SPTBN2	NM_001437541.1		c.5340C>G	p.Asn1780Lys	missense	Exon 26 of 37	NP_001424470.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.5340C>G	p.Asn1780Lys	missense	Exon 27 of 38	ENSP00000432568.1
SPTBN2	ENST00000309996.7	TSL:1	c.5340C>G	p.Asn1780Lys	missense	Exon 26 of 37	ENSP00000311489.2
SPTBN2	ENST00000617502.5	TSL:5	c.5361C>G	p.Asn1787Lys	missense	Exon 25 of 36	ENSP00000482000.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Benign

0.051

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.1

PhyloP100

0.11

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.48

MutPred

0.52

Gain of ubiquitination at N1780 (P = 0.0203)

MVP

0.85

MPC

1.3

ClinPred

1.0

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.82

gMVP

0.82

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over