rs886041027

Positions:

• chr6-107921806-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_007214.5(SEC63):​c.442_443insA​(p.Ala148AspfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SEC63 NM_007214.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.23

Genes affected

SEC63 (HGNC:21082): (SEC63 homolog, protein translocation regulator) The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-107921806-G-GT is Pathogenic according to our data. Variant chr6-107921806-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 2168.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEC63	NM_007214.5	c.442_443insA	p.Ala148AspfsTer8	frameshift_variant	4/21	ENST00000369002.9	NP_009145.1
SEC63	XM_047418130.1	c.274_275insA	p.Ala92AspfsTer8	frameshift_variant	4/21		XP_047274086.1
SEC63	XM_047418131.1	c.22_23insA	p.Ala8AspfsTer8	frameshift_variant	3/20		XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC63	ENST00000369002.9	c.442_443insA	p.Ala148AspfsTer8	frameshift_variant	4/21	1	NM_007214.5	ENSP00000357998	P1
SEC63	ENST00000429168.1	c.274_275insA	p.Ala92AspfsTer8	frameshift_variant	4/8	5		ENSP00000403144
SEC63	ENST00000484803.5	n.364_365insA		non_coding_transcript_exon_variant	4/7	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic liver disease 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

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: rs886041027; hg19: chr6-108243010;