11-66704803-T-C

Variant names:

• chr11-66704803-T-C
• rs4930388
• NM_006946.4:c.2473A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006946.4(SPTBN2):​c.2473A>G​(p.Ser825Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,605,840 control chromosomes in the GnomAD database, including 799,413 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74456 hom., cov: 36)
  • Exomes 𝑓: 1.0 (724957 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.18
• Publications: 25 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):

• autosomal recessive spinocerebellar ataxia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• spinocerebellar ataxia type 5

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.237503E-7).
• BP6: Variant 11-66704803-T-C is Benign according to our data. Variant chr11-66704803-T-C is described in ClinVar as Benign. ClinVar VariationId is 285565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.2473A>G	p.Ser825Gly	missense	Exon 15 of 38	NP_008877.2
	SPTBN2	NM_001411025.1		c.2494A>G	p.Ser832Gly	missense	Exon 13 of 36	NP_001397954.1
	SPTBN2	NM_001437541.1		c.2473A>G	p.Ser825Gly	missense	Exon 14 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.2473A>G	p.Ser825Gly	missense	Exon 15 of 38	ENSP00000432568.1
	SPTBN2	ENST00000309996.7	TSL:1	c.2473A>G	p.Ser825Gly	missense	Exon 14 of 37	ENSP00000311489.2
	SPTBN2	ENST00000617502.5	TSL:5	c.2494A>G	p.Ser832Gly	missense	Exon 13 of 36	ENSP00000482000.2

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150483 AN: 152240 Hom.: 74398 Cov.: 36

Gnomad AFR AF: 0.960

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.997 AC: 235946 AN: 236580 AF XY: 0.998

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1451667 AN: 1453482 Hom.: 724957 Cov.: 106 AF XY: 0.999 AC XY: 722556 AN XY: 723376

African (AFR) AF: 0.961 AC: 32126 AN: 33436

American (AMR) AF: 0.998 AC: 44515 AN: 44612

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26058 AN: 26058

East Asian (EAS) AF: 1.00 AC: 39656 AN: 39656

South Asian (SAS) AF: 1.00 AC: 86117 AN: 86130

European-Finnish (FIN) AF: 1.00 AC: 46533 AN: 46534

Middle Eastern (MID) AF: 0.996 AC: 5736 AN: 5760

European-Non Finnish (NFE) AF: 1.00 AC: 1110910 AN: 1111104

Other (OTH) AF: 0.997 AC: 60016 AN: 60192

GnomAD4 genome AF: 0.988 AC: 150600 AN: 152358 Hom.: 74456 Cov.: 36 AF XY: 0.989 AC XY: 73724 AN XY: 74510

African (AFR) AF: 0.961 AC: 39945 AN: 41586

American (AMR) AF: 0.995 AC: 15239 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10632 AN: 10632

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68009 AN: 68038

Other (OTH) AF: 0.993 AC: 2096 AN: 2110

Alfa AF: 0.995 Hom.: 43812

Bravo AF: 0.987

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.966 AC: 4216

ESP6500EA AF: 1.00 AC: 8541

ExAC AF: 0.996 AC: 119294

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive spinocerebellar ataxia 14 (1)
-	-	1	Spinocerebellar ataxia type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.36
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.047	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.17
Sift	Benign	0.79	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.37
ClinPred		0.0019	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.13
Mutation Taster		=100/0	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: rs4930388; hg19: chr11-66472274; COSMIC: COSV59450435;