rs639938

Variant names:

• chr11-66693056-C-T
• rs639938
• NM_006946.4:c.4899G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006946.4(SPTBN2):​c.4899G>A​(p.Leu1633Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,613,912 control chromosomes in the GnomAD database, including 3,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (379 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2824 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.33
• Publications: 15 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-66693056-C-T is Benign according to our data. Variant chr11-66693056-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

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.4899G>A	p.Leu1633Leu	synonymous	Exon 25 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.4920G>A	p.Leu1640Leu	synonymous	Exon 23 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.4899G>A	p.Leu1633Leu	synonymous	Exon 24 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.4899G>A	p.Leu1633Leu	synonymous	Exon 25 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.4899G>A	p.Leu1633Leu	synonymous	Exon 24 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.4920G>A	p.Leu1640Leu	synonymous	Exon 23 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9499 AN: 152170 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0555

GnomAD2 exomes AF: 0.0678 AC: 17031 AN: 251096 AF XY: 0.0668

Gnomad AFR exome AF: 0.0521

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0567

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0561 AC: 82046 AN: 1461624 Hom.: 2824 Cov.: 33 AF XY: 0.0564 AC XY: 41025 AN XY: 727122

African (AFR) AF: 0.0521 AC: 1744 AN: 33480

American (AMR) AF: 0.0574 AC: 2568 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 689 AN: 26136

East Asian (EAS) AF: 0.107 AC: 4262 AN: 39700

South Asian (SAS) AF: 0.0664 AC: 5726 AN: 86254

European-Finnish (FIN) AF: 0.136 AC: 7224 AN: 53164

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5764

European-Non Finnish (NFE) AF: 0.0507 AC: 56333 AN: 1112010

Other (OTH) AF: 0.0566 AC: 3419 AN: 60396

GnomAD4 genome AF: 0.0625 AC: 9522 AN: 152288 Hom.: 379 Cov.: 32 AF XY: 0.0664 AC XY: 4946 AN XY: 74460

African (AFR) AF: 0.0533 AC: 2215 AN: 41570

American (AMR) AF: 0.0599 AC: 917 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.114 AC: 592 AN: 5182

South Asian (SAS) AF: 0.0751 AC: 363 AN: 4832

European-Finnish (FIN) AF: 0.146 AC: 1546 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0542 AC: 3685 AN: 68004

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0526 Hom.: 584

Bravo AF: 0.0539

Asia WGS AF: 0.125 AC: 433 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	SPTBN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.2
DANN	Benign	0.67
PhyloP100		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs639938; hg19: chr11-66460527; COSMIC: COSV59447137; COSMIC: COSV59447137;