chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Position:

• chr14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

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

The NM_004993.6(ATXN3):​c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG​(p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln) 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 0.013 (50 hom., cov: 20)
  • Exomes 𝑓: 0.0055 (67 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 sas. gnomad4 allele frequency = 0.0132 (1878/142482) while in subpopulation SAS AF= 0.0195 (84/4310). AF 95% confidence interval is 0.0161. There are 50 homozygotes in gnomad4. There are 995 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1878 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	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_916insCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln305_Gly306insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln	inframe_insertion	10/11		NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 1874 AN: 142372 Hom.: 50 Cov.: 20

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00551 AC: 7232 AN: 1312732 Hom.: 67 Cov.: 92 AF XY: 0.00607 AC XY: 3981 AN XY: 656288

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00711

GnomAD4 genome AF: 0.0132 AC: 1878 AN: 142482 Hom.: 50 Cov.: 20 AF XY: 0.0144 AC XY: 995 AN XY: 69220

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0258

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0307

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0168

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;