2-241653601-C-G

Variant names:

• chr2-241653601-C-G
• rs1464289611
• NM_013325.5:c.274C>G

Variant summary

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

The NM_013325.5(ATG4B):​c.274C>G​(p.Leu92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,790 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ATG4B NM_013325.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.197

Genes affected

ATG4B (HGNC:20790): (autophagy related 4B cysteine peptidase) Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
ATG4B	NM_013325.5	c.274C>G	p.Leu92Val	missense_variant	Exon 4 of 13	ENST00000404914.8	NP_037457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4B	ENST00000404914.8	c.274C>G	p.Leu92Val	missense_variant	Exon 4 of 13	1	NM_013325.5	ENSP00000384259.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000583 AC: 1 AN: 171634 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 91588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413790 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 698630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000254 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;D;T;.;T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;D;.;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.8	M;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D
Polyphen		0.65, 0.70	.;P;P;.;.;.;.;.
Vest4		0.46
MutPred		0.89		Gain of MoRF binding (P = 0.11);.;Gain of MoRF binding (P = 0.11);.;Gain of MoRF binding (P = 0.11);Gain of MoRF binding (P = 0.11);.;.;
MVP		0.40
MPC		0.73
ClinPred		0.78	D
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.79

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: rs1464289611; hg19: chr2-242593016;