12-6935973-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001940.4(ATN1):c.706A>C(p.Lys236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,590,362 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0061 (40 hom.)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.09

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008096933).
• BP6: Variant 12-6935973-A-C is Benign according to our data. Variant chr12-6935973-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 982646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.706A>C	p.Lys236Gln	missense_variant	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.706A>C	p.Lys236Gln	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.706A>C	p.Lys236Gln	missense_variant	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.706A>C	p.Lys236Gln	missense_variant	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 152002 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00354 AC: 798 AN: 225474 Hom.: 6 AF XY: 0.00352 AC XY: 430 AN XY: 122082

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.000394

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000751

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00608 AC: 8742 AN: 1438242 Hom.: 40 Cov.: 38 AF XY: 0.00585 AC XY: 4178 AN XY: 713588

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.000250

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.000858

Gnomad4 NFE exome AF: 0.00736

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00384 AC: 584 AN: 152120 Hom.: 2 Cov.: 31 AF XY: 0.00359 AC XY: 267 AN XY: 74356

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00639

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00548 Hom.: 6

Bravo AF: 0.00429

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000922 AC: 4

ESP6500EA AF: 0.00550 AC: 47

ExAC AF: 0.00319 AC: 387

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

ATN1: BS2 -

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.70
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.50	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.61	T;T
Polyphen		0.010	B;B
Vest4		0.23
MVP		0.50
MPC		0.078
ClinPred		0.022	T
GERP RS		2.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200232074; hg19: chr12-7045136;