dbSNP rs1569556: SEC63:c.340-8T>C (chr6-107921917-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007214.5(SEC63):c.340-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00051 ( 2 hom. )

Consequence

SEC63
NM_007214.5 splice_region, intron

Scores

Splicing: ADA: 0.00001260

Clinical Significance

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

Conservation

PhyloP100: -1.01

Publications

3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 6-107921917-A-G is Benign according to our data. Variant chr6-107921917-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 23 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC63	NM_007214.5	MANE Select	c.340-8T>C		splice_region intron	N/A	NP_009145.1	Q9UGP8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SEC63	ENST00000369002.9	TSL:1 MANE Select	c.340-8T>C	splice_region intron	N/A	ENSP00000357998.4	Q9UGP8
SEC63	ENST00000884697.1		c.427-8T>C	splice_region intron	N/A	ENSP00000554756.1
SEC63	ENST00000884696.1		c.421-8T>C	splice_region intron	N/A	ENSP00000554755.1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

AN:

11668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.0156

GnomAD2 exomes

AF:

0.000334

AC:

AN:

179464

AF XY:

0.000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00746

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000829

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.000508

AC:

192

AN:

377862

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

194252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9218

American (AMR)

AF:

0.0000712

AC:

AN:

14036

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

150

AN:

8316

East Asian (EAS)

AF:

0.00

AC:

AN:

11902

South Asian (SAS)

AF:

0.0000391

AC:

AN:

25544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1260

European-Non Finnish (NFE)

AF:

0.0000687

AC:

AN:

276392

Other (OTH)

AF:

0.00131

AC:

AN:

16088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00197

AC:

AN:

11668

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

AN XY:

5562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1496

American (AMR)

AF:

0.00

AC:

AN:

880

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

AN:

146

East Asian (EAS)

AF:

0.00

AC:

AN:

260

South Asian (SAS)

AF:

0.00

AC:

AN:

114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000267

AC:

AN:

7478

Other (OTH)

AF:

0.0156

AC:

AN:

128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.247

Hom.:

180

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Polycystic liver disease 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.82

(source)

DANN

Benign

0.45

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

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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

Computational scores

Splicing

Publications

Other links and lift over