Genetic Variant SEC63:c.340-7T>A (chr6-107921916-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007214.5(SEC63):c.340-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SEC63
NM_007214.5 splice_region, intron

Scores

Splicing: ADA: 0.0003885

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.208

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

SEC63 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SEC63	NM_007214.5 link	c.340-7T>A	splice_region_variant, intron_variant	Intron 3 of 20	ENST00000369002.9	NP_009145.1	Q9UGP8A0A0S2Z5M1
SEC63	XM_047418130.1 link	c.172-7T>A	splice_region_variant, intron_variant	Intron 3 of 20		XP_047274086.1
SEC63	XM_047418131.1 link	c.-81-7T>A	splice_region_variant, intron_variant	Intron 2 of 19		XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SEC63	ENST00000369002.9 link	c.340-7T>A	splice_region_variant, intron_variant	Intron 3 of 20	1	NM_007214.5	ENSP00000357998.4	Q9UGP8
SEC63	ENST00000429168.1 link	c.172-7T>A	splice_region_variant, intron_variant	Intron 3 of 7	5		ENSP00000403144.1	A6PVC9
SEC63	ENST00000484803.5 link	n.262-7T>A	splice_region_variant, intron_variant	Intron 3 of 6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1023444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

518642

African (AFR)

AF:

0.00

AC:

AN:

23626

American (AMR)

AF:

0.00

AC:

AN:

34882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20860

East Asian (EAS)

AF:

0.00

AC:

AN:

32650

South Asian (SAS)

AF:

0.00

AC:

AN:

66020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4492

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

755748

Other (OTH)

AF:

0.00

AC:

AN:

43652

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.4

(source)

DANN

Benign

0.63

PhyloP100

0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over