rs61733388

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.20

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

polycystic liver disease 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
polycystic liver disease 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SEC63 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 260153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 2527 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007214.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC63	NM_007214.5	MANE Select	c.2027C>T	p.Thr676Ile	missense	Exon 19 of 21	NP_009145.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SEC63	ENST00000369002.9	TSL:1 MANE Select	c.2027C>T	p.Thr676Ile	missense	Exon 19 of 21	ENSP00000357998.4
SEC63	ENST00000459782.1	TSL:1	n.830C>T		non_coding_transcript_exon	Exon 1 of 3
SEC63	ENST00000473746.1	TSL:2	n.674C>T		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes

AF:

0.0174

AC:

4368

AN:

250980

AF XY:

0.0177

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 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

African (AFR)

AF:

0.00397

AC:

130

AN:

32774

American (AMR)

AF:

0.0115

AC:

509

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

738

AN:

25638

East Asian (EAS)

AF:

0.0000512

AC:

AN:

39066

South Asian (SAS)

AF:

0.00282

AC:

241

AN:

85606

European-Finnish (FIN)

AF:

0.0192

AC:

1002

AN:

52164

Middle Eastern (MID)

AF:

0.0201

AC:

AN:

4234

European-Non Finnish (NFE)

AF:

0.0255

AC:

27701

AN:

1087672

Other (OTH)

AF:

0.0188

AC:

1107

AN:

58940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1259

2518

3778

5037

6296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1000

2000

3000

4000

5000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0172

AC:

2527

AN:

147314

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1146

AN XY:

71360

show subpopulations

African (AFR)

AF:

0.00488

AC:

194

AN:

39746

American (AMR)

AF:

0.0121

AC:

172

AN:

14244

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4886

South Asian (SAS)

AF:

0.00323

AC:

AN:

4650

European-Finnish (FIN)

AF:

0.0172

AC:

165

AN:

9570

Middle Eastern (MID)

AF:

0.0221

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0271

AC:

1827

AN:

67524

Other (OTH)

AF:

0.0185

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

131

262

392

523

654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0238

Hom.:

174

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Polycystic liver disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

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

PhyloP100

2.2

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over