rs143948660

chr11-66701195-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006946.4(SPTBN2):c.2904G>A(p.Thr968=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,613,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-66701195-C-T is Benign according to our data. Variant chr11-66701195-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 448489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66701195-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000722 (1054/1460832) while in subpopulation SAS AF= 0.00155 (134/86258). AF 95% confidence interval is 0.00134. There are 1 homozygotes in gnomad4_exome. There are 544 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN2	NM_006946.4	c.2904G>A	p.Thr968=	synonymous_variant	17/38	ENST00000533211.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN2	ENST00000533211.6	c.2904G>A	p.Thr968=	synonymous_variant	17/38	5	NM_006946.4	P1

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00127 AC: 317 AN: 249158 Hom.: 0 AF XY: 0.00129 AC XY: 174 AN XY: 135356

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000722 AC: 1054 AN: 1460832 Hom.: 1 Cov.: 33 AF XY: 0.000749 AC XY: 544 AN XY: 726748

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00487

Gnomad4 NFE exome AF: 0.000515

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152336 Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74494

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00575

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000656 Hom.: 0

Bravo AF: 0.000355

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SPTBN2: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.53
Dann	Benign	0.67

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: rs143948660; hg19: chr11-66468666; COSMIC: COSV100020113; COSMIC: COSV100020113;