11-66744819-GGGCGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr11-66744819-G-GGGCGGCGGCGGCGGCGGC
• rs567536854
• NM_001302084.2:c.-121_-104dupCGGCGGCGGCGGCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001302084.2(TOP6BL):​c.-121_-104dupCGGCGGCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.00096 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00033 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 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.-121_-104dupCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-62_-45dupCGGCGGCGGCGGCGGCGG		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.-121_-104dupCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525908.6	TSL:2	c.-62_-45dupCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 17	ENSP00000432039.3	A0A2U3TZP7
	TOP6BL	ENST00000901160.1		c.-121_-104dupCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	ENSP00000571219.1

Frequencies

GnomAD3 genomes AF: 0.000965 AC: 143 AN: 148182 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000814

Gnomad SAS AF: 0.00191

Gnomad FIN AF: 0.000102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000814

Gnomad OTH AF: 0.000981

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000333 AC: 360 AN: 1081804 Hom.: 0 Cov.: 31 AF XY: 0.000340 AC XY: 178 AN XY: 523236

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

African (AFR) AF: 0.0000431 AC: 1 AN: 23218

American (AMR) AF: 0.000170 AC: 2 AN: 11750

Ashkenazi Jewish (ASJ) AF: 0.0000641 AC: 1 AN: 15596

East Asian (EAS) AF: 0.000532 AC: 14 AN: 26292

South Asian (SAS) AF: 0.000508 AC: 16 AN: 31484

European-Finnish (FIN) AF: 0.000158 AC: 4 AN: 25360

Middle Eastern (MID) AF: 0.000266 AC: 1 AN: 3762

European-Non Finnish (NFE) AF: 0.000341 AC: 307 AN: 900344

Other (OTH) AF: 0.000318 AC: 14 AN: 43998

⚠️ 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: 0.000964 AC: 143 AN: 148284 Hom.: 2 Cov.: 0 AF XY: 0.00104 AC XY: 75 AN XY: 72246

African (AFR) AF: 0.000245 AC: 10 AN: 40786

American (AMR) AF: 0.00420 AC: 63 AN: 15016

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

East Asian (EAS) AF: 0.000816 AC: 4 AN: 4900

South Asian (SAS) AF: 0.00191 AC: 9 AN: 4706

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9840

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

European-Non Finnish (NFE) AF: 0.000814 AC: 54 AN: 66368

Other (OTH) AF: 0.000971 AC: 2 AN: 2060

Alfa AF: 0.00 Hom.: 682

Bravo AF: 0.000718

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;