rs752018806

Positions:

• chr6-107883115-ACTT-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000369002.9(SEC63):​c.1703_1705del​(p.Glu568del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0025 in 1,612,242 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (16 hom.)
• Consequence: SEC63 ENST00000369002.9 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• Conservation: PhyloP100: 6.33

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 6-107883115-ACTT-A is Benign according to our data. Variant chr6-107883115-ACTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 354899.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}. Variant chr6-107883115-ACTT-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00261 (397/152262) while in subpopulation NFE AF= 0.00219 (149/68022). AF 95% confidence interval is 0.0019. There are 5 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 397 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEC63	NM_007214.5	c.1703_1705del	p.Glu568del	inframe_deletion	17/21	ENST00000369002.9	NP_009145.1
SEC63	XM_047418130.1	c.1535_1537del	p.Glu512del	inframe_deletion	17/21		XP_047274086.1
SEC63	XM_047418131.1	c.1283_1285del	p.Glu428del	inframe_deletion	16/20		XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC63	ENST00000369002.9	c.1703_1705del	p.Glu568del	inframe_deletion	17/21	1	NM_007214.5	ENSP00000357998	P1
SEC63	ENST00000473746.1	n.350_352del		non_coding_transcript_exon_variant	1/4	2
SEC63	ENST00000465210.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152144 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00369 AC: 926 AN: 250706 Hom.: 5 AF XY: 0.00356 AC XY: 483 AN XY: 135556

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00249 AC: 3640 AN: 1459980 Hom.: 16 AF XY: 0.00244 AC XY: 1770 AN XY: 726412

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152262 Hom.: 5 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74448

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00454 Hom.: 0

Bravo AF: 0.00153

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic liver disease 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Polycystic liver disease 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

SEC63-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs752018806; hg19: chr6-108204319;