rs34775878

Variant names:

• chr11-66714162-G-A
• rs34775878
• NM_006946.4:c.585C>T

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.585C>T​(p.Asn195Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,584 control chromosomes in the GnomAD database, including 9,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (729 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8736 hom.)
• Consequence: SPTBN2 NM_006946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.946
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet
• autosomal recessive spinocerebellar ataxia 14

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-66714162-G-A is Benign according to our data. Variant chr11-66714162-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.946 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.585C>T	p.Asn195Asn	synonymous	Exon 7 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.606C>T	p.Asn202Asn	synonymous	Exon 5 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.585C>T	p.Asn195Asn	synonymous	Exon 6 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.585C>T	p.Asn195Asn	synonymous	Exon 7 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.585C>T	p.Asn195Asn	synonymous	Exon 6 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.606C>T	p.Asn202Asn	synonymous	Exon 5 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12163 AN: 152196 Hom.: 728 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0814 AC: 20466 AN: 251456 AF XY: 0.0840

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0694

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.103 AC: 149905 AN: 1461270 Hom.: 8736 Cov.: 33 AF XY: 0.102 AC XY: 74007 AN XY: 726964

African (AFR) AF: 0.0202 AC: 677 AN: 33476

American (AMR) AF: 0.0725 AC: 3242 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3283 AN: 26128

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0452 AC: 3902 AN: 86254

European-Finnish (FIN) AF: 0.0354 AC: 1889 AN: 53410

Middle Eastern (MID) AF: 0.142 AC: 818 AN: 5768

European-Non Finnish (NFE) AF: 0.117 AC: 129828 AN: 1111424

Other (OTH) AF: 0.104 AC: 6254 AN: 60388

GnomAD4 genome AF: 0.0798 AC: 12158 AN: 152314 Hom.: 729 Cov.: 32 AF XY: 0.0766 AC XY: 5705 AN XY: 74486

African (AFR) AF: 0.0218 AC: 905 AN: 41580

American (AMR) AF: 0.0968 AC: 1481 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4824

European-Finnish (FIN) AF: 0.0304 AC: 323 AN: 10614

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8211 AN: 68016

Other (OTH) AF: 0.101 AC: 214 AN: 2116

Alfa AF: 0.107 Hom.: 501

Bravo AF: 0.0838

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.134

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.0
DANN	Benign	0.86
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34775878; hg19: chr11-66481633;