NM_006946.4:c.1719C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_006946.4(SPTBN2):c.1719C>T(p.His573His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,612,492 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 9 hom. )

Consequence

SPTBN2
NM_006946.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.115

Publications

3 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 11-66705772-G-A is Benign according to our data. Variant chr11-66705772-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194240.

BP7

Synonymous conserved (PhyloP=-0.115 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000414 (605/1460164) while in subpopulation MID AF = 0.0229 (132/5768). AF 95% confidence interval is 0.0197. There are 9 homozygotes in GnomAdExome4. There are 322 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.1719C>T	p.His573His	synonymous_variant	Exon 14 of 38	ENST00000533211.6	NP_008877.2	O15020-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6 link	c.1719C>T	p.His573His	synonymous_variant	Exon 14 of 38	5	NM_006946.4	ENSP00000432568.1		O15020-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000360

AC:

AN:

244678

AF XY:

0.000411

show subpopulations

Gnomad AFR exome

AF:

0.000325

Gnomad AMR exome

AF:

0.000234

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.0000554

Gnomad FIN exome

AF:

0.0000965

Gnomad NFE exome

AF:

0.000463

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000414

AC:

605

AN:

1460164

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

322

AN XY:

726372

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33472

American (AMR)

AF:

0.000291

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000371

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.0000767

AC:

AN:

52130

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5768

European-Non Finnish (NFE)

AF:

0.000308

AC:

343

AN:

1111858

Other (OTH)

AF:

0.000729

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.000394

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000509

Hom.:

Bravo

AF:

0.000370

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 16, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 25, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant cerebellar ataxia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.9

(source)

DANN

Benign

0.51

PhyloP100

-0.12

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over