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rs116078747

chr11-66707825-C-Achr11-66707825-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006946.4(SPTBN2):c.1351-7G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,607,658 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00002262
2

Clinical Significance

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

Conservation

PhyloP100: -1.01
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-66707825-C-A is Benign according to our data. Variant chr11-66707825-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 305587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66707825-C-A is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1620/152272) while in subpopulation AFR AF= 0.0365 (1516/41554). AF 95% confidence interval is 0.035. There are 39 homozygotes in gnomad4. There are 759 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 38 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTBN2NM_006946.4 linkuse as main transcriptc.1351-7G>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000533211.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTBN2ENST00000533211.6 linkuse as main transcriptc.1351-7G>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 NM_006946.4 P1O15020-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0106
AC:
1617
AN:
152154
Hom.:
38
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0365
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00504
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:
0.00623
GnomAD3 exomes
AF:
0.00298
AC:
724
AN:
243132
Hom.:
15
AF XY:
0.00223
AC XY:
296
AN XY:
132618
show subpopulations
Gnomad AFR exome
AF:
0.0389
Gnomad AMR exome
AF:
0.00226
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000137
Gnomad OTH exome
AF:
0.00133
GnomAD4 exome
AF:
0.00111
AC:
1622
AN:
1455386
Hom.:
33
Cov.:
32
AF XY:
0.000968
AC XY:
701
AN XY:
724180
show subpopulations
Gnomad4 AFR exome
AF:
0.0374
Gnomad4 AMR exome
AF:
0.00257
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000468
Gnomad4 OTH exome
AF:
0.00305
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0106
AC:
1620
AN:
152272
Hom.:
39
Cov.:
33
AF XY:
0.0102
AC XY:
759
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.0365
Gnomad4 AMR
AF:
0.00503
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00616
Alfa
AF:
0.000468
Hom.:
1
Bravo
AF:
0.0120
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeJan 17, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 06, 2022See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 10, 2017- -
Autosomal recessive spinocerebellar ataxia 14 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Spinocerebellar ataxia type 5 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
0.27
Dann
Benign
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000023
dbscSNV1_RF
Benign
0.0060
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs116078747; hg19: chr11-66475296; API