14-92071010-C-CCTGCTG

Position:

• chr14-92071010-C-CCTGCTG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004993.6(ATXN3):​c.915_916insCAGCAG​(p.Gln304_Gln305dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,456,778 control chromosomes in the GnomAD database, including 43 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00062 (43 hom.)
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 14-92071010-C-CCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTG is described in ClinVar as [Benign]. Clinvar id is 599464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAG	p.Gln304_Gln305dup	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_916insCAGCAG	p.Gln304_Gln305dup	inframe_insertion	10/11		NM_004993.6	ENSP00000496695	P1

Frequencies

GnomAD3 genomes AF: 0.000449 AC: 64 AN: 142396 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000764

Gnomad ASJ AF: 0.000586

Gnomad EAS AF: 0.000431

Gnomad SAS AF: 0.00162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000512

Gnomad OTH AF: 0.000515

GnomAD4 exome AF: 0.000618 AC: 812 AN: 1314272 Hom.: 43 Cov.: 92 AF XY: 0.000645 AC XY: 424 AN XY: 657142

Gnomad4 AFR exome AF: 0.000545

Gnomad4 AMR exome AF: 0.000864

Gnomad4 ASJ exome AF: 0.000164

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.0000409

Gnomad4 NFE exome AF: 0.000577

Gnomad4 OTH exome AF: 0.000726

GnomAD4 genome AF: 0.000449 AC: 64 AN: 142506 Hom.: 0 Cov.: 20 AF XY: 0.000506 AC XY: 35 AN XY: 69232

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000763

Gnomad4 ASJ AF: 0.000586

Gnomad4 EAS AF: 0.000432

Gnomad4 SAS AF: 0.00162

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000512

Gnomad4 OTH AF: 0.000510

Bravo AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

May 03, 2017

Normal variation in repetative sequence -

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;