rs2241880

Positions:

• chr2-233274722-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000392017.9(ATG16L1):​c.898A>G​(p.Thr300Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,609,114 control chromosomes in the GnomAD database, including 203,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15195 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188220 hom.)
• Consequence: ATG16L1 ENST00000392017.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.448

Genes affected

ATG16L1 (HGNC:21498): (autophagy related 16 like 1) The protein encoded by this gene is part of a large protein complex that is necessary for autophagy, the major process by which intracellular components are targeted to lysosomes for degradation. Defects in this gene are a cause of susceptibility to inflammatory bowel disease type 10 (IBD10). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8645105E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG16L1	NM_030803.7	c.898A>G	p.Thr300Ala	missense_variant	9/18	ENST00000392017.9	NP_110430.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG16L1	ENST00000392017.9	c.898A>G	p.Thr300Ala	missense_variant	9/18	1	NM_030803.7	ENSP00000375872	P3

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66455 AN: 151798 Hom.: 15197 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.528

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.453 AC: 113606 AN: 250652 Hom.: 27569 AF XY: 0.469 AC XY: 63500 AN XY: 135462

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.502 AC: 730915 AN: 1457198 Hom.: 188220 Cov.: 36 AF XY: 0.504 AC XY: 365648 AN XY: 725132

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.442

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.437 AC: 66454 AN: 151916 Hom.: 15195 Cov.: 32 AF XY: 0.432 AC XY: 32071 AN XY: 74208

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.438

Alfa AF: 0.506 Hom.: 49100

Bravo AF: 0.423

TwinsUK AF: 0.524 AC: 1942

ALSPAC AF: 0.520 AC: 2005

ESP6500AA AF: 0.324 AC: 1428

ESP6500EA AF: 0.524 AC: 4506

ExAC AF: 0.457 AC: 55525

Asia WGS AF: 0.359 AC: 1250 AN: 3478

EpiCase AF: 0.531

EpiControl AF: 0.522

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 24, 2015

- -

ATG16L1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Inflammatory bowel disease 10, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 27, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.62
DANN	Benign	0.71
DEOGEN2	Benign	0.017	.;T;T;.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
MetaRNN	Benign	0.000019	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	.;N;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.61	T;T;T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;.;B;.;B;.
Vest4		0.049
MPC		0.56
ClinPred		0.017	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2241880; hg19: chr2-234183368; COSMIC: COSV61464428; COSMIC: COSV61464428;