rs61741217

Variant names:

• chr11-66686024-C-T
• rs61741217
• NM_006946.4:c.7020G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006946.4(SPTBN2):​c.7020G>A​(p.Pro2340Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,682 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (20 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.29
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• autosomal recessive spinocerebellar ataxia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-66686024-C-T is Benign according to our data. Variant chr11-66686024-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00887 (1350/152258) while in subpopulation AFR AF = 0.0302 (1255/41542). AF 95% confidence interval is 0.0288. There are 23 homozygotes in GnomAd4. There are 612 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	NM_006946.4	MANE Select	c.7020G>A	p.Pro2340Pro	synonymous	Exon 38 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.7041G>A	p.Pro2347Pro	synonymous	Exon 36 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.7020G>A	p.Pro2340Pro	synonymous	Exon 37 of 37	NP_001424470.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN2	ENST00000533211.6	TSL:5 MANE Select	c.7020G>A	p.Pro2340Pro	synonymous	Exon 38 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.7020G>A	p.Pro2340Pro	synonymous	Exon 37 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.7041G>A	p.Pro2347Pro	synonymous	Exon 36 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes AF: 0.00885 AC: 1347 AN: 152140 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00250 AC: 622 AN: 248670 AF XY: 0.00167

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000957 AC: 1399 AN: 1461424 Hom.: 20 Cov.: 31 AF XY: 0.000802 AC XY: 583 AN XY: 727040

African (AFR) AF: 0.0321 AC: 1074 AN: 33480

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111994

Other (OTH) AF: 0.00207 AC: 125 AN: 60388

GnomAD4 genome AF: 0.00887 AC: 1350 AN: 152258 Hom.: 23 Cov.: 32 AF XY: 0.00822 AC XY: 612 AN XY: 74456

African (AFR) AF: 0.0302 AC: 1255 AN: 41542

American (AMR) AF: 0.00451 AC: 69 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00441 Hom.: 7

Bravo AF: 0.0112

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 5 (1)
-	-	1	SPTBN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.46
DANN	Benign	0.43
PhyloP100		-2.3
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs61741217; hg19: chr11-66453495; COSMIC: COSV59455170; COSMIC: COSV59455170;