rs145249947

chr11-66707753-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_006946.4(SPTBN2):c.1416G>A(p.Thr472=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,607,594 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.99

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-66707753-C-T is Benign according to our data. Variant chr11-66707753-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 487360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66707753-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00227 (346/152332) while in subpopulation AFR AF= 0.0077 (320/41576). AF 95% confidence interval is 0.007. There are 0 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.1416G>A	p.Thr472=	synonymous_variant	13/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.1416G>A	p.Thr472=	synonymous_variant	13/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000754 AC: 185 AN: 245392 Hom.: 1 AF XY: 0.000615 AC XY: 82 AN XY: 133366

Gnomad AFR exome AF: 0.00873

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.000210

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000390 AC: 568 AN: 1455262 Hom.: 5 Cov.: 32 AF XY: 0.000381 AC XY: 276 AN XY: 723850

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000823

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74498

Gnomad4 AFR AF: 0.00770

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 16, 2023

- -

Spinocerebellar ataxia type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.1
Dann	Benign	0.90

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

LitVar

Other links and lift over

dbSNP: rs145249947; hg19: chr11-66475224;