rs147993402

chr12-6935675-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001940.4(ATN1):c.408C>T(p.Tyr136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,614,012 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0076 (60 hom.)
• Consequence: ATN1 NM_001940.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.987

Genes affected

ATN1 (HGNC:3033): (atrophin 1) Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-6935675-C-T is Benign according to our data. Variant chr12-6935675-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.987 with no splicing effect.
• BS2: High AC in GnomAd at 738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.408C>T	p.Tyr136=	synonymous_variant	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.408C>T	p.Tyr136=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.408C>T	p.Tyr136=	synonymous_variant	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.408C>T	p.Tyr136=	synonymous_variant	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152110 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00828

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00436 AC: 1095 AN: 251382 Hom.: 8 AF XY: 0.00414 AC XY: 563 AN XY: 135866

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00754

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00764 AC: 11166 AN: 1461784 Hom.: 60 Cov.: 38 AF XY: 0.00737 AC XY: 5363 AN XY: 727214

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00935

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.00485 AC: 738 AN: 152228 Hom.: 4 Cov.: 31 AF XY: 0.00458 AC XY: 341 AN XY: 74450

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00828

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00669 Hom.: 2

Bravo AF: 0.00480

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00872

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

ATN1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	9.3
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs147993402; hg19: chr12-7044838;