11-66744819-GGGCGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr11-66744819-G-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC
• rs567536854
• NM_001302084.2:c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001302084.2(TOP6BL):​c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 148,182 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00015 (0 hom., cov: 0)
• Consequence: TOP6BL NM_001302084.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 4 publications found

Genes affected

TOP6BL (HGNC:26197): (TOP6B like initiator of meiotic double strand breaks) Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302084.2. 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
	TOP6BL	NM_001302084.2	MANE Select	c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-45_-44insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 17	NP_078926.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525908.6	TSL:2	c.-45_-44insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 17	ENSP00000432039.3	A0A2U3TZP7
	TOP6BL	ENST00000901160.1		c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000571219.1

Frequencies

GnomAD3 genomes AF: 0.000148 AC: 22 AN: 148182 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.000491

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.000148 AC: 22 AN: 148182 Hom.: 0 Cov.: 0 AF XY: 0.000111 AC XY: 8 AN XY: 72136

African (AFR) AF: 0.0000246 AC: 1 AN: 40672

American (AMR) AF: 0.00113 AC: 17 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4916

South Asian (SAS) AF: 0.00 AC: 0 AN: 4714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66378

Other (OTH) AF: 0.000491 AC: 1 AN: 2038

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=92/8	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs567536854; hg19: chr11-66512290;