rs61733388

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007214.5(SEC63):c.2027C>T(p.Thr676Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,577,850 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 30)

Exomes 𝑓: 0.022 ( 427 hom. )

Consequence

SEC63
NM_007214.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.20

Variant links:

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]

SEC63 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006633669).

BP6

Variant 6-107876571-G-A is Benign according to our data. Variant chr6-107876571-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-107876571-G-A is described in Lovd as [Benign]. Variant chr6-107876571-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2527/147314) while in subpopulation NFE AF= 0.0271 (1827/67524). AF 95% confidence interval is 0.026. There are 27 homozygotes in gnomad4. There are 1146 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SEC63	NM_007214.5 linkuse as main transcript	c.2027C>T	p.Thr676Ile	missense_variant	19/21	ENST00000369002.9	NP_009145.1
SEC63	XM_047418130.1 linkuse as main transcript	c.1859C>T	p.Thr620Ile	missense_variant	19/21		XP_047274086.1
SEC63	XM_047418131.1 linkuse as main transcript	c.1607C>T	p.Thr536Ile	missense_variant	18/20		XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SEC63	ENST00000369002.9 linkuse as main transcript	c.2027C>T	p.Thr676Ile	missense_variant	19/21	1	NM_007214.5	ENSP00000357998	P1
SEC63	ENST00000459782.1 linkuse as main transcript	n.830C>T		non_coding_transcript_exon_variant	1/3	1
SEC63	ENST00000473746.1 linkuse as main transcript	n.674C>T		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2529

AN:

147240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00489

Gnomad AMI

AF:

0.0396

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0214

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00322

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.0272

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0174

AC:

4368

AN:

250980

Hom.:

AF XY:

0.0177

AC XY:

2406

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0260

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0220

AC:

31515

AN:

1430536

Hom.:

427

Cov.:

AF XY:

0.0216

AC XY:

15422

AN XY:

713366

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.0115

Gnomad4 ASJ exome

AF:

0.0288

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.00282

Gnomad4 FIN exome

AF:

0.0192

Gnomad4 NFE exome

AF:

0.0255

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0172

AC:

2527

AN:

147314

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1146

AN XY:

71360

show subpopulations

Gnomad4 AFR

AF:

0.00488

Gnomad4 AMR

AF:

0.0121

Gnomad4 ASJ

AF:

0.0214

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00323

Gnomad4 FIN

AF:

0.0172

Gnomad4 NFE

AF:

0.0271

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0247

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0267

AC:

230

ExAC

AF:

0.0178

AC:

2166

Asia WGS

AF:

0.00289

AC:

AN:

3476

EpiCase

AF:

0.0266

EpiControl

AF:

0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic liver disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.064

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.71

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Benign

0.20

Sift4G

Benign

0.15

Polyphen

0.10

Vest4

0.089

MPC

0.34

ClinPred

0.012

GERP RS

1.6

Varity_R

0.026

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over