NM_001302084.2:c.-30+5T>C

Variant names:

• chr11-66744924-T-C
• rs574408551
• NM_001302084.2:c.-30+5T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001302084.2(TOP6BL):​c.-30+5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,254,476 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 30)
  • Exomes 𝑓: 0.010 (70 hom.)
• Consequence: TOP6BL NM_001302084.2 splice_region, intron
• Scores: Splicing: ADA: 0.003980
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.360
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-66744924-T-C is Benign according to our data. Variant chr11-66744924-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3055893.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0103 (11303/1102516) while in subpopulation SAS AF = 0.0211 (462/21874). AF 95% confidence interval is 0.0195. There are 70 homozygotes in GnomAdExome4. There are 5414 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.-30+5T>C		splice_region intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.30+5T>C		splice_region intron	N/A	NP_078926.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.-30+5T>C		splice_region intron	N/A	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000901167.1		c.-307T>C		5_prime_UTR	Exon 1 of 17	ENSP00000571226.1
	TOP6BL	ENST00000901168.1		c.-126T>C		5_prime_UTR	Exon 1 of 15	ENSP00000571227.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1112 AN: 151842 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00995

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.0135 AC: 262 AN: 19442 AF XY: 0.0140

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00991

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.0103 AC: 11303 AN: 1102516 Hom.: 70 Cov.: 33 AF XY: 0.0104 AC XY: 5414 AN XY: 522804

African (AFR) AF: 0.00113 AC: 26 AN: 23010

American (AMR) AF: 0.00460 AC: 39 AN: 8472

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 103 AN: 14382

East Asian (EAS) AF: 0.0000753 AC: 2 AN: 26572

South Asian (SAS) AF: 0.0211 AC: 462 AN: 21874

European-Finnish (FIN) AF: 0.0204 AC: 718 AN: 35270

Middle Eastern (MID) AF: 0.00833 AC: 38 AN: 4562

European-Non Finnish (NFE) AF: 0.0103 AC: 9562 AN: 924316

Other (OTH) AF: 0.00801 AC: 353 AN: 44058

GnomAD4 genome AF: 0.00733 AC: 1114 AN: 151960 Hom.: 8 Cov.: 30 AF XY: 0.00778 AC XY: 578 AN XY: 74296

African (AFR) AF: 0.00181 AC: 75 AN: 41464

American (AMR) AF: 0.00295 AC: 45 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4824

European-Finnish (FIN) AF: 0.0187 AC: 197 AN: 10546

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00995 AC: 676 AN: 67932

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00835 Hom.: 3

Bravo AF: 0.00600

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.79
PhyloP100		0.36
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs574408551; hg19: chr11-66512395;