14-92071010-CCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Position:

• chr14-92071010-CCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0049 (46 hom., cov: 20)
  • Exomes 𝑓: 0.00033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168

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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (699/142366) while in subpopulation AFR AF= 0.0167 (603/36188). AF 95% confidence interval is 0.0156. There are 46 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 699 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11	ENST00000644486.2	NP_004984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11		NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 696 AN: 142256 Hom.: 46 Cov.: 20

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00278

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000464

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000482

Gnomad OTH AF: 0.00567

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000329 AC: 432 AN: 1313984 Hom.: 0 Cov.: 92 AF XY: 0.000307 AC XY: 202 AN XY: 657032

Gnomad4 AFR exome AF: 0.00931

Gnomad4 AMR exome AF: 0.000494

Gnomad4 ASJ exome AF: 0.0000410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000365

Gnomad4 FIN exome AF: 0.000327

Gnomad4 NFE exome AF: 0.0000723

Gnomad4 OTH exome AF: 0.000636

GnomAD4 genome AF: 0.00491 AC: 699 AN: 142366 Hom.: 46 Cov.: 20 AF XY: 0.00489 AC XY: 338 AN XY: 69162

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00278

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000464

Gnomad4 FIN AF: 0.00111

Gnomad4 NFE AF: 0.000482

Gnomad4 OTH AF: 0.00561

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: rs193922928; hg19: chr14-92537354;