14-92071009-C-CGCTGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004993.6(ATXN3):c.916_917insAGCAGCAGC(p.Gly306delinsGluGlnGlnArg) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 779,480 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: ATXN3 NM_004993.6 protein_altering
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.916_917insAGCAGCAGC	p.Gly306delinsGluGlnGlnArg	protein_altering_variant	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.916_917insAGCAGCAGC	p.Gly306delinsGluGlnGlnArg	protein_altering_variant	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000257 AC: 2 AN: 779480 Hom.: 0 Cov.: 50 AF XY: 0.00000254 AC XY: 1 AN XY: 393818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000293

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000172

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs763461489; hg19: chr14-92537353;