rs146137419

Variant names:

• chr11-66694224-A-G
• rs146137419
• NM_006946.4:c.4418T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS1

The NM_006946.4(SPTBN2):​c.4418T>C​(p.Leu1473Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.56
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• BP6: Variant 11-66694224-A-G is Benign according to our data. Variant chr11-66694224-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448503.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000274 (40/1461748) while in subpopulation AFR AF = 0.00111 (37/33480). AF 95% confidence interval is 0.000824. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4418T>C	p.Leu1473Ser	missense	Exon 22 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.4439T>C	p.Leu1480Ser	missense	Exon 20 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.4418T>C	p.Leu1473Ser	missense	Exon 21 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.4418T>C	p.Leu1473Ser	missense	Exon 22 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.4418T>C	p.Leu1473Ser	missense	Exon 21 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.4439T>C	p.Leu1480Ser	missense	Exon 20 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251272 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727188

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74494

African (AFR) AF: 0.000866 AC: 36 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000494 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.83
MPC		1.1
ClinPred		0.56	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.78
Mutation Taster		=71/29	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: rs146137419; hg19: chr11-66461695;