dbSNP rs34275473: SPTBN2:p.Leu337Leu (chr11-66710644-A-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006946.4(SPTBN2):c.1011T>G(p.Leu337Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,164 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 33 hom. )

Consequence

SPTBN2
NM_006946.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.682

Publications

1 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):

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

SPTBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 11-66710644-A-C is Benign according to our data. Variant chr11-66710644-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.682 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1640/152318) while in subpopulation AFR AF = 0.0369 (1535/41580). AF 95% confidence interval is 0.0354. There are 39 homozygotes in GnomAd4. There are 770 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR gene

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	UniProt
SPTBN2	NM_006946.4	MANE Select	c.1011T>G	p.Leu337Leu	synonymous	Exon 10 of 38	NP_008877.2	O15020-1
SPTBN2	NM_001411025.1		c.1032T>G	p.Leu344Leu	synonymous	Exon 8 of 36	NP_001397954.1	A0A087WYQ1
SPTBN2	NM_001437541.1		c.1011T>G	p.Leu337Leu	synonymous	Exon 9 of 37	NP_001424470.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.1011T>G	p.Leu337Leu	synonymous	Exon 10 of 38	ENSP00000432568.1	O15020-1
SPTBN2	ENST00000309996.7	TSL:1	c.1011T>G	p.Leu337Leu	synonymous	Exon 9 of 37	ENSP00000311489.2	O15020-1
SPTBN2	ENST00000617502.5	TSL:5	c.1032T>G	p.Leu344Leu	synonymous	Exon 8 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1637

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0370

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00293

AC:

735

AN:

250772

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.0391

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00112

AC:

1630

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

703

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0376

AC:

1260

AN:

33480

American (AMR)

AF:

0.00257

AC:

115

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111992

Other (OTH)

AF:

0.00306

AC:

185

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0108

AC:

1640

AN:

152318

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

770

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0369

AC:

1535

AN:

41580

American (AMR)

AF:

0.00510

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68020

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal dominant cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.7

(source)

DANN

Benign

0.71

PhyloP100

0.68

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over