dbSNP rs778218574: SPTBN2:p.Arg1841Pro (chr11-66691327-C-G) – 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.5522G>C(p.Arg1841Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1841Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPTBN2
NM_006946.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.370

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:

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.5522G>C	p.Arg1841Pro	missense_variant	Exon 27 of 38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 link	c.5522G>C	p.Arg1841Pro	missense_variant	Exon 27 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1401132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32386

American (AMR)

AF:

0.00

AC:

AN:

39552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22162

East Asian (EAS)

AF:

0.00

AC:

AN:

39000

South Asian (SAS)

AF:

0.00

AC:

AN:

76444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077820

Other (OTH)

AF:

0.00

AC:

AN:

57714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

0.0098

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;.

Eigen

Benign

-0.011

Eigen_PC

Benign

-0.037

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.2

L;L;L

PhyloP100

0.37

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.089

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.83

P;P;.

Vest4

0.57

MutPred

0.68

Loss of stability (P = 0.1363);Loss of stability (P = 0.1363);Loss of stability (P = 0.1363);

MVP

0.51

MPC

1.3

ClinPred

0.80

GERP RS

3.8

Varity_R

0.60

gMVP

0.76

Mutation Taster

=68/32

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over