11-66744819-G-GGGC

Variant names:

• chr11-66744819-G-GGGC
• rs567536854
• NM_001302084.2:c.-106_-104dupCGG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001302084.2(TOP6BL):​c.-106_-104dupCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,222,560 control chromosomes in the GnomAD database, including 109,539 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.44 (15707 hom., cov: 0)
  • Exomes 𝑓: 0.47 (93832 hom.)
• Consequence: TOP6BL NM_001302084.2 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• 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 -9 ACMG points.

• BP6: Variant 11-66744819-G-GGGC is Benign according to our data. Variant chr11-66744819-G-GGGC is described in ClinVar as Benign. ClinVar VariationId is 3058840.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.603 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.-106_-104dupCGG		5_prime_UTR	Exon 1 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.-47_-45dupCGG		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.-106_-104dupCGG		5_prime_UTR	Exon 1 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525908.6	TSL:2	c.-47_-45dupCGG		5_prime_UTR	Exon 1 of 17	ENSP00000432039.3	A0A2U3TZP7
	TOP6BL	ENST00000901160.1		c.-106_-104dupCGG		5_prime_UTR	Exon 1 of 15	ENSP00000571219.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 65659 AN: 148046 Hom.: 15705 Cov.: 0

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.519 AC: 7822 AN: 15072 AF XY: 0.534

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.471 AC: 506279 AN: 1074412 Hom.: 93832 Cov.: 31 AF XY: 0.473 AC XY: 245711 AN XY: 519658

African (AFR) AF: 0.232 AC: 5367 AN: 23168

American (AMR) AF: 0.349 AC: 3900 AN: 11188

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 6861 AN: 15520

East Asian (EAS) AF: 0.388 AC: 10180 AN: 26262

South Asian (SAS) AF: 0.572 AC: 17933 AN: 31362

European-Finnish (FIN) AF: 0.464 AC: 11583 AN: 24986

Middle Eastern (MID) AF: 0.448 AC: 1682 AN: 3752

European-Non Finnish (NFE) AF: 0.479 AC: 428889 AN: 894458

Other (OTH) AF: 0.455 AC: 19884 AN: 43716

GnomAD4 genome AF: 0.443 AC: 65664 AN: 148148 Hom.: 15707 Cov.: 0 AF XY: 0.445 AC XY: 32097 AN XY: 72162

African (AFR) AF: 0.263 AC: 10711 AN: 40748

American (AMR) AF: 0.401 AC: 6004 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1668 AN: 3422

East Asian (EAS) AF: 0.412 AC: 2015 AN: 4892

South Asian (SAS) AF: 0.622 AC: 2921 AN: 4694

European-Finnish (FIN) AF: 0.521 AC: 5108 AN: 9812

Middle Eastern (MID) AF: 0.507 AC: 146 AN: 288

European-Non Finnish (NFE) AF: 0.537 AC: 35605 AN: 66348

Other (OTH) AF: 0.460 AC: 949 AN: 2062

Alfa AF: 0.268 Hom.: 682

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TOP6BL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=91/9	polymorphism (auto)

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: COSV60929265; COSMIC: COSV60929265;