17-42818407-A-C

Variant names:

• chr17-42818407-A-C
• NM_001313998.2:c.497T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001313998.2(BECN1):​c.497T>G​(p.Leu166Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BECN1 NM_001313998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

Genes affected

BECN1 (HGNC:1034): (beclin 1) This gene encodes a protein that regulates autophagy, a catabolic process of degradation induced by starvation. The encoded protein is a component of the phosphatidylinositol-3-kinase (PI3K) complex which mediates vesicle-trafficking processes. This protein is thought to play a role in multiple cellular processes, including tumorigenesis, neurodegeneration and apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BECN1	NM_001313998.2	c.497T>G	p.Leu166Trp	missense_variant	Exon 7 of 12	ENST00000590099.6	NP_001300927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BECN1	ENST00000590099.6	c.497T>G	p.Leu166Trp	missense_variant	Exon 7 of 12	1	NM_001313998.2	ENSP00000465364.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497T>G (p.L166W) alteration is located in exon 7 (coding exon 6) of the BECN1 gene. This alteration results from a T to G substitution at nucleotide position 497, causing the leucine (L) at amino acid position 166 to be replaced by a tryptophan (W). 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	0.81
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D;D;T;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Pathogenic	3.2	M;M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	D;.;D;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.;D;.;.
Sift4G	Uncertain	0.058	T;T;D;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.84
MutPred		0.68		Loss of ubiquitination at K163 (P = 0.0787);Loss of ubiquitination at K163 (P = 0.0787);.;.;.;
MVP		0.70
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40970425;