Genetic Variant TOP6BL:c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGG (chr11-66744819-G-GGGCGGCGGCGGCGGCGGCGGCGGCGGC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001302084.2(TOP6BL):c.-104_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGG 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 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOP6BL
NM_001302084.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

4 publications found

Variant links:

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]

TOP6BL links:

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)

SPTBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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_-103insCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-45_-44insCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 17	NP_078926.4

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.000148

AC:

AN:

148182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.000424

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000241

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000110

AC:

119

AN:

1082244

Hom.:

Cov.:

AF XY:

0.0000974

AC XY:

AN XY:

523432

show subpopulations

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

African (AFR)

AF:

0.0000431

AC:

AN:

23216

American (AMR)

AF:

0.00

AC:

AN:

11748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15596

East Asian (EAS)

AF:

0.00

AC:

AN:

26298

South Asian (SAS)

AF:

0.0000952

AC:

AN:

31500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.000123

AC:

111

AN:

900754

Other (OTH)

AF:

0.0000909

AC:

AN:

44004

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.327

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000148

AC:

AN:

148284

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

72246

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40786

American (AMR)

AF:

0.000133

AC:

AN:

15016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3424

East Asian (EAS)

AF:

0.000204

AC:

AN:

4900

South Asian (SAS)

AF:

0.000425

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000241

AC:

AN:

66368

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

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

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-66744819-GGGCGGCGGCGGCGGC-GGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over