rs1569557

Variant names:

• chr6-107921916-A-G
• rs1569557
• NM_007214.5:c.340-7T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-107921916-A-G
• chr6-107921916-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007214.5(SEC63):​c.340-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,146,240 control chromosomes in the GnomAD database, including 10 homozygotes. 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 0.00085 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00049 (9 hom.)
• Consequence: SEC63 NM_007214.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002116
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.208
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-107921916-A-G is Benign according to our data. Variant chr6-107921916-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000845 (104/123016) while in subpopulation AFR AF = 0.00149 (44/29588). AF 95% confidence interval is 0.00114. There are 1 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 104 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.340-7T>C		splice_region intron	N/A	NP_009145.1	Q9UGP8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC63	ENST00000369002.9	TSL:1 MANE Select	c.340-7T>C		splice_region intron	N/A	ENSP00000357998.4	Q9UGP8
	SEC63	ENST00000884697.1		c.427-7T>C		splice_region intron	N/A	ENSP00000554756.1
	SEC63	ENST00000884696.1		c.421-7T>C		splice_region intron	N/A	ENSP00000554755.1

Frequencies

GnomAD3 genomes AF: 0.000805 AC: 99 AN: 122998 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.00629

Gnomad EAS AF: 0.000466

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00699

Gnomad NFE AF: 0.000399

Gnomad OTH AF: 0.00284

GnomAD2 exomes AF: 0.000509 AC: 106 AN: 208188 AF XY: 0.000476

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.000359

Gnomad ASJ exome AF: 0.00623

Gnomad EAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000403

GnomAD4 exome AF: 0.000491 AC: 502 AN: 1023224 Hom.: 9 Cov.: 16 AF XY: 0.000511 AC XY: 265 AN XY: 518542

African (AFR) AF: 0.00212 AC: 50 AN: 23624

American (AMR) AF: 0.000717 AC: 25 AN: 34860

Ashkenazi Jewish (ASJ) AF: 0.00734 AC: 153 AN: 20854

East Asian (EAS) AF: 0.0000306 AC: 1 AN: 32644

South Asian (SAS) AF: 0.0000909 AC: 6 AN: 65994

European-Finnish (FIN) AF: 0.0000482 AC: 2 AN: 41510

Middle Eastern (MID) AF: 0.000890 AC: 4 AN: 4492

European-Non Finnish (NFE) AF: 0.000246 AC: 186 AN: 755596

Other (OTH) AF: 0.00172 AC: 75 AN: 43650

GnomAD4 genome AF: 0.000845 AC: 104 AN: 123016 Hom.: 1 Cov.: 26 AF XY: 0.00102 AC XY: 61 AN XY: 59924

African (AFR) AF: 0.00149 AC: 44 AN: 29588

American (AMR) AF: 0.000592 AC: 8 AN: 13522

Ashkenazi Jewish (ASJ) AF: 0.00629 AC: 20 AN: 3178

East Asian (EAS) AF: 0.000467 AC: 2 AN: 4280

South Asian (SAS) AF: 0.00 AC: 0 AN: 4054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7896

Middle Eastern (MID) AF: 0.00763 AC: 2 AN: 262

European-Non Finnish (NFE) AF: 0.000399 AC: 23 AN: 57700

Other (OTH) AF: 0.00282 AC: 5 AN: 1774

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Polycystic liver disease 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.63
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs1569557; hg19: chr6-108243120;