11-66690113-G-C

Position:

• chr11-66690113-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_006946.4(SPTBN2):​c.5736C>G​(p.Phe1912Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (1 hom.)
• Consequence: SPTBN2 NM_006946.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 8.09

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN2. . Gene score misZ 2.6349 (greater than the threshold 3.09). Trascript score misZ 4.499 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive spinocerebellar ataxia 14, spinocerebellar ataxia type 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36164543).
• BP6: Variant 11-66690113-G-C is Benign according to our data. Variant chr11-66690113-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.5736C>G	p.Phe1912Leu	missense_variant	28/38	ENST00000533211.6	NP_008877.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN2	ENST00000533211.6	c.5736C>G	p.Phe1912Leu	missense_variant	28/38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152268 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251162 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135788

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000581

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152386 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74528

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000567

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPTBN2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 448516). This variant has not been reported in the literature in individuals affected with SPTBN2-related conditions. This variant is present in population databases (rs202247290, gnomAD 0.03%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1912 of the SPTBN2 protein (p.Phe1912Leu). -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	3.0	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.022	D;D;D
Sift4G	Benign	0.075	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.79		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.80
MPC		1.3
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.77

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: rs202247290; hg19: chr11-66457584;