rs148207416

chr11-66705772-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_006946.4(SPTBN2):c.1719C>T(p.His573=) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.115

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 -8 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 id is 194240.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.115 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 322 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.1719C>T	p.His573=	synonymous_variant	14/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.1719C>T	p.His573=	synonymous_variant	14/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152210 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000360 AC: 88 AN: 244678 Hom.: 0 AF XY: 0.000411 AC XY: 55 AN XY: 133680

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 SAS exome AF: 0.000198

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.: 9 Cov.: 35 AF XY: 0.000443 AC XY: 322 AN XY: 726372

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000767

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74500

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000370

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 25, 2020

- -

Autosomal dominant cerebellar ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	1.9
Dann	Benign	0.51

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: rs148207416; hg19: chr11-66473243; COSMIC: COSV100019975;