Genetic Variant NM_006946.4:c.3516C>G (chr11-66700583-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006946.4(SPTBN2):c.3516C>G(p.His1172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H1172Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.796

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.3516C>G	p.His1172Gln	missense	Exon 17 of 38	NP_008877.2
SPTBN2	NM_001411025.1		c.3537C>G	p.His1179Gln	missense	Exon 15 of 36	NP_001397954.1
SPTBN2	NM_001437541.1		c.3516C>G	p.His1172Gln	missense	Exon 16 of 37	NP_001424470.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.3516C>G	p.His1172Gln	missense	Exon 17 of 38	ENSP00000432568.1
SPTBN2	ENST00000309996.7	TSL:1	c.3516C>G	p.His1172Gln	missense	Exon 16 of 37	ENSP00000311489.2
SPTBN2	ENST00000617502.5	TSL:5	c.3537C>G	p.His1179Gln	missense	Exon 15 of 36	ENSP00000482000.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

0.057

MutationAssessor

Uncertain

2.0

PhyloP100

-0.80

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.41

Sift

Benign

0.041

Sift4G

Benign

0.43

Polyphen

1.0

Vest4

0.51

MutPred

0.44

Gain of disorder (P = 0.034)

MVP

0.49

MPC

1.1

ClinPred

0.84

GERP RS

-9.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.087

gMVP

0.26

Mutation Taster

=88/12

polymorphism

(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