17-42818868-GG-AA

Variant names:

• chr17-42818868-GG-AA
• NM_001313998.2:c.269_270delCCinsTT
• BECN1 p.Ser90Phe

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001313998.2(BECN1):​c.269_270delCCinsTT​(p.Ser90Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BECN1 NM_001313998.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.64
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a mutagenesis_site Complete loss of phosphorylation. Complete loss of phosphorylation and defective autophagic function; when associated with Ala-93. (size 0) in uniprot entity BECN1_HUMAN
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001313998.2. 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
	BECN1	NM_001313998.2	MANE Select	c.269_270delCCinsTT	p.Ser90Phe	missense	N/A	NP_001300927.1	A0A024R1X5
	BECN1	NM_003766.5		c.269_270delCCinsTT	p.Ser90Phe	missense	N/A	NP_003757.1	A0A024R1X5
	BECN1	NM_001313999.1		c.269_270delCCinsTT	p.Ser90Phe	missense	N/A	NP_001300928.1	W0FFG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BECN1	ENST00000590099.6	TSL:1 MANE Select	c.269_270delCCinsTT	p.Ser90Phe	missense	N/A	ENSP00000465364.1	Q14457
	BECN1	ENST00000361523.8	TSL:1	c.269_270delCCinsTT	p.Ser90Phe	missense	N/A	ENSP00000355231.3	Q14457
	BECN1	ENST00000893295.1		c.407_408delCCinsTT	p.Ser136Phe	missense	N/A	ENSP00000563354.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-40970886;