chr14-92071010-C-CCTGCTG

Variant names:

• chr14-92071010-C-CCTGCTG
• rs193922928
• NM_004993.6:c.910_915dupCAGCAG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_004993.6(ATXN3):​c.910_915dupCAGCAG​(p.Gln304_Gln305dup) variant causes a conservative 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 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

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]

ATXN3 Gene-Disease associations (from GenCC):

• Machado-Joseph disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Machado-Joseph disease type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Machado-Joseph disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004993.6
• BP6: Variant 14-92071010-C-CCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 599464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 64 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004993.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	NM_004993.6	MANE Select	c.910_915dupCAGCAG	p.Gln304_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	NP_004984.2
	ATXN3	NM_001127696.2		c.865_870dupCAGCAG	p.Gln289_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	NP_001121168.1
	ATXN3	NM_001127697.3		c.757_762dupCAGCAG	p.Gln253_Gln254dup	conservative_inframe_insertion	Exon 8 of 9	NP_001121169.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN3	ENST00000644486.2	MANE Select	c.910_915dupCAGCAG	p.Gln304_Gln305dup	conservative_inframe_insertion	Exon 10 of 11	ENSP00000496695.1
	ATXN3	ENST00000532032.5	TSL:1	c.910_915dupCAGCAG	p.Gln304_Gln305dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000437157.1
	ATXN3	ENST00000503767.5	TSL:1	c.865_870dupCAGCAG	p.Gln289_Gln290dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000426697.1

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

African (AFR) AF: 0.000545 AC: 15 AN: 27502

American (AMR) AF: 0.000864 AC: 35 AN: 40496

Ashkenazi Jewish (ASJ) AF: 0.000164 AC: 4 AN: 24396

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37452

South Asian (SAS) AF: 0.00138 AC: 110 AN: 79488

European-Finnish (FIN) AF: 0.0000409 AC: 2 AN: 48902

Middle Eastern (MID) AF: 0.00524 AC: 27 AN: 5148

European-Non Finnish (NFE) AF: 0.000577 AC: 575 AN: 995786

Other (OTH) AF: 0.000726 AC: 40 AN: 55102

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

African (AFR) AF: 0.000193 AC: 7 AN: 36314

American (AMR) AF: 0.000763 AC: 11 AN: 14414

Ashkenazi Jewish (ASJ) AF: 0.000586 AC: 2 AN: 3412

East Asian (EAS) AF: 0.000432 AC: 2 AN: 4634

South Asian (SAS) AF: 0.00162 AC: 7 AN: 4310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000512 AC: 34 AN: 66414

Other (OTH) AF: 0.000510 AC: 1 AN: 1962

Alfa AF: 0.00 Hom.: 345

Bravo AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 03, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Normal variation in repetative sequence

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354;