Genetic Variant ATG2A:p.Arg566His (chr11-64910626-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_015104.3(ATG2A):c.1697G>A(p.Arg566His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,601,918 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0063 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 94 hom. )

Consequence

ATG2A
NM_015104.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.605

Publications

7 publications found

Variant links:

Genes affected

ATG2A (HGNC:29028): (autophagy related 2A) Predicted to enable phosphatidylinositol-3-phosphate binding activity. Involved in autophagosome assembly. Predicted to be located in endoplasmic reticulum membrane; lipid droplet; and phagophore assembly site membrane. Predicted to be active in phagophore assembly site. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATG2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020740032).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00627 (955/152276) while in subpopulation EAS AF = 0.025 (129/5168). AF 95% confidence interval is 0.0215. There are 12 homozygotes in GnomAd4. There are 592 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG2A	NM_015104.3 link	c.1697G>A	p.Arg566His	missense_variant	Exon 12 of 41	ENST00000377264.8	NP_055919.2	Q2TAZ0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG2A	ENST00000377264.8 link	c.1697G>A	p.Arg566His	missense_variant	Exon 12 of 41	1	NM_015104.3	ENSP00000366475.3		Q2TAZ0-1
ATG2A	ENST00000418259.5 link	c.1100G>A	p.Arg367His	missense_variant	Exon 8 of 37	5		ENSP00000413716.1		H7C3T2

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

955

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0249

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0427

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00423

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00709

AC:

1615

AN:

227782

AF XY:

0.00696

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.000862

Gnomad ASJ exome

AF:

0.000209

Gnomad EAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0386

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00638

GnomAD4 exome

AF:

0.00419

AC:

6079

AN:

1449642

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

3053

AN XY:

720226

show subpopulations

African (AFR)

AF:

0.000271

AC:

AN:

33190

American (AMR)

AF:

0.00137

AC:

AN:

43120

Ashkenazi Jewish (ASJ)

AF:

0.000386

AC:

AN:

25896

East Asian (EAS)

AF:

0.0350

AC:

1363

AN:

38932

South Asian (SAS)

AF:

0.00104

AC:

AN:

84308

European-Finnish (FIN)

AF:

0.0376

AC:

1944

AN:

51682

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00216

AC:

2390

AN:

1106862

Other (OTH)

AF:

0.00352

AC:

211

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

385

770

1154

1539

1924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00627

AC:

955

AN:

152276

Hom.:

Cov.:

AF XY:

0.00795

AC XY:

592

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41560

American (AMR)

AF:

0.00281

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0250

AC:

129

AN:

5168

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0427

AC:

453

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00423

AC:

288

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00452

Hom.:

Bravo

AF:

0.00324

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00373

AC:

ExAC

AF:

0.00601

AC:

727

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

0.60

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

REVEL

Benign

0.030

Sift

Benign

0.10

Sift4G

Benign

0.22

Polyphen

0.0040

Vest4

0.31

MVP

0.082

MPC

0.19

ClinPred

0.0088

GERP RS

3.1

Varity_R

0.028

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over