rs114788199

Variant names:

• chr11-66699496-T-C
• rs114788199
• NM_006946.4:c.3686A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006946.4(SPTBN2):​c.3686A>G​(p.His1229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,190 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (18 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0160
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002019912).
• BP6: Variant 11-66699496-T-C is Benign according to our data. Variant chr11-66699496-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00756 (1152/152298) while in subpopulation AFR AF = 0.0258 (1074/41554). AF 95% confidence interval is 0.0246. There are 14 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.3686A>G	p.His1229Arg	missense	Exon 18 of 38	NP_008877.2	O15020-1
	SPTBN2	NM_001411025.1		c.3707A>G	p.His1236Arg	missense	Exon 16 of 36	NP_001397954.1	A0A087WYQ1
	SPTBN2	NM_001437541.1		c.3686A>G	p.His1229Arg	missense	Exon 17 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.3686A>G	p.His1229Arg	missense	Exon 18 of 38	ENSP00000432568.1	O15020-1
	SPTBN2	ENST00000309996.7	TSL:1	c.3686A>G	p.His1229Arg	missense	Exon 17 of 37	ENSP00000311489.2	O15020-1
	SPTBN2	ENST00000617502.5	TSL:5	c.3707A>G	p.His1236Arg	missense	Exon 16 of 36	ENSP00000482000.2	A0A087WYQ1

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1150 AN: 152180 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00202 AC: 508 AN: 251486 AF XY: 0.00141

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000751 AC: 1098 AN: 1461892 Hom.: 18 Cov.: 31 AF XY: 0.000652 AC XY: 474 AN XY: 727246

African (AFR) AF: 0.0271 AC: 908 AN: 33480

American (AMR) AF: 0.00181 AC: 81 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: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112012

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.00756 AC: 1152 AN: 152298 Hom.: 14 Cov.: 32 AF XY: 0.00787 AC XY: 586 AN XY: 74488

African (AFR) AF: 0.0258 AC: 1074 AN: 41554

American (AMR) AF: 0.00392 AC: 60 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00268 Hom.: 15

Bravo AF: 0.00817

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00258 AC: 313

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.3
DANN	Benign	0.17
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.016
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.024
Sift	Benign	0.61	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.12
MPC		0.50
ClinPred		0.00060	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.036
gMVP		0.074
Mutation Taster		=98/2	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: rs114788199; hg19: chr11-66466967;