Genetic Variant SPTBN2:c.*546T>C (chr11-66685325-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_006946.4(SPTBN2):c.*546T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 164,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0032 ( 1 hom. )

Consequence

SPTBN2
NM_006946.4 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.972

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-66685325-A-G is Benign according to our data. Variant chr11-66685325-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 305517.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (388/141856) while in subpopulation NFE AF = 0.00477 (313/65550). AF 95% confidence interval is 0.00434. There are 0 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4 link	c.*546T>C		3_prime_UTR_variant	Exon 38 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.*546T>C		3_prime_UTR_variant	Exon 38 of 38	5	NM_006946.4	ENSP00000432568.1		O15020-1

Frequencies

GnomAD3 genomes

AF:

0.00274

AC:

388

AN:

141772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000597

Gnomad AMI

AF:

0.00457

Gnomad AMR

AF:

0.000496

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00429

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00477

Gnomad OTH

AF:

0.00201

GnomAD4 exome

AF:

0.00324

AC:

AN:

22204

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

AN XY:

11446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

462

American (AMR)

AF:

0.00

AC:

AN:

2836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

366

East Asian (EAS)

AF:

0.00

AC:

AN:

1192

South Asian (SAS)

AF:

0.00

AC:

AN:

2818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00542

AC:

AN:

12542

Other (OTH)

AF:

0.00359

AC:

AN:

1114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00274

AC:

388

AN:

141856

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

168

AN XY:

68602

show subpopulations

African (AFR)

AF:

0.000596

AC:

AN:

38574

American (AMR)

AF:

0.000495

AC:

AN:

14146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00

AC:

AN:

4304

South Asian (SAS)

AF:

0.00

AC:

AN:

4124

European-Finnish (FIN)

AF:

0.00429

AC:

AN:

8628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00477

AC:

313

AN:

65550

Other (OTH)

AF:

0.00199

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00323

Hom.:

Bravo

AF:

0.00227

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

-0.84

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

0.97

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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11-66685325-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over