NM_001302084.2:c.-112_-104dupCGGCGGCGG

Variant names:

• chr11-66744819-G-GGGCGGCGGC
• rs567536854
• NM_001302084.2:c.-112_-104dupCGGCGGCGG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001302084.2(TOP6BL):​c.-112_-104dupCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00881 in 1,227,660 control chromosomes in the GnomAD database, including 86 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 0)
  • Exomes 𝑓: 0.0084 (65 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.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.012 (1774/148276) while in subpopulation AMR AF = 0.0242 (364/15014). AF 95% confidence interval is 0.0222. There are 21 homozygotes in GnomAd4. There are 911 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.-112_-104dupCGGCGGCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-53_-45dupCGGCGGCGG		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.-112_-104dupCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525908.6	TSL:2	c.-53_-45dupCGGCGGCGG		5_prime_UTR	Exon 1 of 17	ENSP00000432039.3	A0A2U3TZP7
	TOP6BL	ENST00000901160.1		c.-112_-104dupCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000571219.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1771 AN: 148174 Hom.: 21 Cov.: 0

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.00759

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00742

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.00940

Gnomad OTH AF: 0.00932

GnomAD2 exomes AF: 0.00285 AC: 43 AN: 15072 AF XY: 0.00285

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000926

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00838 AC: 9041 AN: 1079384 Hom.: 65 Cov.: 31 AF XY: 0.00847 AC XY: 4421 AN XY: 522116

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0123 AC: 284 AN: 23108

American (AMR) AF: 0.0180 AC: 211 AN: 11736

Ashkenazi Jewish (ASJ) AF: 0.00546 AC: 85 AN: 15576

East Asian (EAS) AF: 0.0134 AC: 353 AN: 26268

South Asian (SAS) AF: 0.00967 AC: 304 AN: 31444

European-Finnish (FIN) AF: 0.00457 AC: 116 AN: 25358

Middle Eastern (MID) AF: 0.0120 AC: 45 AN: 3758

European-Non Finnish (NFE) AF: 0.00802 AC: 7204 AN: 898254

Other (OTH) AF: 0.0100 AC: 439 AN: 43882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0120 AC: 1774 AN: 148276 Hom.: 21 Cov.: 0 AF XY: 0.0126 AC XY: 911 AN XY: 72240

African (AFR) AF: 0.0136 AC: 553 AN: 40782

American (AMR) AF: 0.0242 AC: 364 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.00759 AC: 26 AN: 3424

East Asian (EAS) AF: 0.0147 AC: 72 AN: 4900

South Asian (SAS) AF: 0.00829 AC: 39 AN: 4706

European-Finnish (FIN) AF: 0.00742 AC: 73 AN: 9840

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.00940 AC: 624 AN: 66366

Other (OTH) AF: 0.00922 AC: 19 AN: 2060

Alfa AF: 0.00240 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

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; COSMIC: COSV107410635;