11-66744819-GGGCGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr11-66744819-G-GGGCGGC
• rs567536854
• NM_001302084.2:c.-109_-104dupCGGCGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001302084.2(TOP6BL):​c.-109_-104dupCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,221,768 control chromosomes in the GnomAD database, including 6,888 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1409 hom., cov: 0)
  • Exomes 𝑓: 0.12 (5479 hom.)
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

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.-109_-104dupCGGCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-50_-45dupCGGCGG		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.-109_-104dupCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525908.6	TSL:2	c.-50_-45dupCGGCGG		5_prime_UTR	Exon 1 of 17	ENSP00000432039.3	A0A2U3TZP7
	TOP6BL	ENST00000901160.1		c.-109_-104dupCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000571219.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17005 AN: 148098 Hom.: 1406 Cov.: 0

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.0919

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.0926

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0452

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0936 AC: 1411 AN: 15072 AF XY: 0.0883

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0831

Gnomad OTH exome AF: 0.0750

GnomAD4 exome AF: 0.122 AC: 130555 AN: 1073568 Hom.: 5479 Cov.: 31 AF XY: 0.121 AC XY: 62940 AN XY: 519386

African (AFR) AF: 0.0442 AC: 1022 AN: 23136

American (AMR) AF: 0.357 AC: 4167 AN: 11672

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 1402 AN: 15542

East Asian (EAS) AF: 0.0357 AC: 937 AN: 26274

South Asian (SAS) AF: 0.0896 AC: 2808 AN: 31346

European-Finnish (FIN) AF: 0.184 AC: 4660 AN: 25298

Middle Eastern (MID) AF: 0.0643 AC: 241 AN: 3746

European-Non Finnish (NFE) AF: 0.124 AC: 110396 AN: 892864

Other (OTH) AF: 0.113 AC: 4922 AN: 43690

GnomAD4 genome AF: 0.115 AC: 17019 AN: 148200 Hom.: 1409 Cov.: 0 AF XY: 0.118 AC XY: 8527 AN XY: 72194

African (AFR) AF: 0.0496 AC: 2021 AN: 40768

American (AMR) AF: 0.264 AC: 3958 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.0926 AC: 317 AN: 3424

East Asian (EAS) AF: 0.0224 AC: 110 AN: 4900

South Asian (SAS) AF: 0.0769 AC: 362 AN: 4706

European-Finnish (FIN) AF: 0.172 AC: 1690 AN: 9820

Middle Eastern (MID) AF: 0.0483 AC: 14 AN: 290

European-Non Finnish (NFE) AF: 0.124 AC: 8241 AN: 66342

Other (OTH) AF: 0.109 AC: 224 AN: 2058

Alfa AF: 0.0731 Hom.: 682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs567536854; hg19: chr11-66512290; COSMIC: COSV60928901; COSMIC: COSV60928901;