rs61733388

chr6-107876571-G-Achr6-107876571-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T676A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (27 hom., cov: 30)
  • Exomes 𝑓: 0.022 (427 hom.)
• Consequence: SEC63 NM_007214.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.20

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 -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 GnomAd at 2529 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC63	NM_007214.5	c.2027C>T	p.Thr676Ile	missense_variant	19/21	ENST00000369002.9
SEC63	XM_047418130.1	c.1859C>T	p.Thr620Ile	missense_variant	19/21
SEC63	XM_047418131.1	c.1607C>T	p.Thr536Ile	missense_variant	18/20

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2529 AN: 147240 Hom.: 27 Cov.: 30

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.: 47 AF XY: 0.0177 AC XY: 2406 AN XY: 135666

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.: 28 AF XY: 0.0216 AC XY: 15422 AN XY: 713366

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.: 27 Cov.: 30 AF XY: 0.0161 AC XY: 1146 AN XY: 71360

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.: 93

Bravo AF: 0.0161

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0267 AC: 230

ExAC AF: 0.0178 AC: 2166

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0266

EpiControl AF: 0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	- -

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	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Polyphen		0.10	B
Vest4		0.089
MPC		0.34
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs61733388; hg19: chr6-108197775; COSMIC: COSV64602823; COSMIC: COSV64602823;