2-241651034-G-C

Variant names:

• chr2-241651034-G-C
• rs1237125437
• NM_013325.5:c.35G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013325.5(ATG4B):​c.35G>C​(p.Arg12Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATG4B NM_013325.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4B	NM_013325.5	MANE Select	c.35G>C	p.Arg12Pro	missense	Exon 2 of 13	NP_037457.3
	ATG4B	NM_178326.3		c.35G>C	p.Arg12Pro	missense	Exon 2 of 13	NP_847896.1	Q9Y4P1-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4B	ENST00000404914.8	TSL:1 MANE Select	c.35G>C	p.Arg12Pro	missense	Exon 2 of 13	ENSP00000384259.3	Q9Y4P1-1
	ATG4B	ENST00000482507.5	TSL:1	n.52G>C		non_coding_transcript_exon	Exon 2 of 13
	ATG4B	ENST00000902606.1		c.218G>C	p.Arg73Pro	missense	Exon 3 of 14	ENSP00000572665.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.44
Sift	Benign	0.29	T
Sift4G	Benign	0.28	T
Polyphen		0.87	P
Vest4		0.95
MutPred		0.46		Loss of helix (P = 0.028)
MVP		0.75
MPC		1.1
ClinPred		0.85	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.93
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1237125437; hg19: chr2-242590449;