12-6935911-C-T

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.644C>T(p.Pro215Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,609,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000071 (1 hom.)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.68

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=0.011096835).
• BP6: Variant 12-6935911-C-T is Benign according to our data. Variant chr12-6935911-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3040448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.644C>T	p.Pro215Leu	missense_variant	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.644C>T	p.Pro215Leu	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.644C>T	p.Pro215Leu	missense_variant	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.644C>T	p.Pro215Leu	missense_variant	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000196 AC: 48 AN: 244966 Hom.: 0 AF XY: 0.000158 AC XY: 21 AN XY: 132516

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000707 AC: 103 AN: 1457602 Hom.: 1 Cov.: 38 AF XY: 0.0000566 AC XY: 41 AN XY: 724840

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000698 AC XY: 52 AN XY: 74456

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.00101

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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

Jul 09, 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. -

ATN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Benign	0.84
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.0	B;B
Vest4		0.33
MVP		0.52
MPC		0.080
ClinPred		0.059	T
GERP RS		3.6
Varity_R		0.091
gMVP		0.12

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: rs139874082; hg19: chr12-7045074;