chr11-66685325-A-G

Variant names:

• chr11-66685325-A-G
• rs539068045
• NM_006946.4:c.*546T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_006946.4(SPTBN2):​c.*546T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 164,060 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0032 (1 hom.)
• Consequence: SPTBN2 NM_006946.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.972
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-66685325-A-G is Benign according to our data. Variant chr11-66685325-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 305517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (388/141856) while in subpopulation NFE AF = 0.00477 (313/65550). AF 95% confidence interval is 0.00434. There are 0 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN2	NM_006946.4	c.*546T>C		3_prime_UTR_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.*546T>C		3_prime_UTR_variant	Exon 38 of 38	5	NM_006946.4	ENSP00000432568.1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 388 AN: 141772 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000597

Gnomad AMI AF: 0.00457

Gnomad AMR AF: 0.000496

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00429

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00477

Gnomad OTH AF: 0.00201

GnomAD4 exome AF: 0.00324 AC: 72 AN: 22204 Hom.: 1 Cov.: 0 AF XY: 0.00306 AC XY: 35 AN XY: 11446

African (AFR) AF: 0.00 AC: 0 AN: 462

American (AMR) AF: 0.00 AC: 0 AN: 2836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 366

East Asian (EAS) AF: 0.00 AC: 0 AN: 1192

South Asian (SAS) AF: 0.00 AC: 0 AN: 2818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 54

European-Non Finnish (NFE) AF: 0.00542 AC: 68 AN: 12542

Other (OTH) AF: 0.00359 AC: 4 AN: 1114

GnomAD4 genome AF: 0.00274 AC: 388 AN: 141856 Hom.: 0 Cov.: 30 AF XY: 0.00245 AC XY: 168 AN XY: 68602

African (AFR) AF: 0.000596 AC: 23 AN: 38574

American (AMR) AF: 0.000495 AC: 7 AN: 14146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4304

South Asian (SAS) AF: 0.00 AC: 0 AN: 4124

European-Finnish (FIN) AF: 0.00429 AC: 37 AN: 8628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00477 AC: 313 AN: 65550

Other (OTH) AF: 0.00199 AC: 4 AN: 2010

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant cerebellar ataxia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.61
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs539068045; hg19: chr11-66452796;