NM_006946.4:c.7103T>A

Variant names:

• chr11-66685941-A-T
• rs1940076270
• NM_006946.4:c.7103T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006946.4(SPTBN2):​c.7103T>A​(p.Val2368Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18234307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.7103T>A	p.Val2368Glu	missense_variant	Exon 38 of 38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.7103T>A	p.Val2368Glu	missense_variant	Exon 38 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	.;T;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.23	N;N;.;.
REVEL	Benign	0.28
Sift	Benign	0.15	T;T;.;.
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		0.84	P;P;.;.
Vest4		0.24
MutPred		0.20		Loss of MoRF binding (P = 0.0441);Loss of MoRF binding (P = 0.0441);.;.;
MVP		0.68
MPC		0.73
ClinPred		0.71	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.14
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1940076270; hg19: chr11-66453412;