11-72822248-G-C

Position:

• chr11-72822248-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000321297.10(ATG16L2):​c.597G>C​(p.Lys199Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,346,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: ATG16L2 ENST00000321297.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.194

Genes affected

ATG16L2 (HGNC:25464): (autophagy related 16 like 2) Predicted to be involved in autophagosome assembly and negative stranded viral RNA replication. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG16L2	NM_033388.2	c.597G>C	p.Lys199Asn	missense_variant	5/18	ENST00000321297.10	NP_203746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG16L2	ENST00000321297.10	c.597G>C	p.Lys199Asn	missense_variant	5/18	1	NM_033388.2	ENSP00000326340	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000427 AC: 4 AN: 93610 Hom.: 0 AF XY: 0.0000760 AC XY: 4 AN XY: 52636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000546

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: 0.00000743 AC: 10 AN: 1346354 Hom.: 0 Cov.: 33 AF XY: 0.00000904 AC XY: 6 AN XY: 663638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000235

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000356

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.597G>C (p.K199N) alteration is located in exon 5 (coding exon 5) of the ATG16L2 gene. This alteration results from a G to C substitution at nucleotide position 597, causing the lysine (K) at amino acid position 199 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.50		Gain of methylation at R201 (P = 0.0866);
MVP		0.79
MPC		3.1
ClinPred		0.65	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.50

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: rs944873805; hg19: chr11-72533293;