rs1555788144

Variant names:

• chr20-18524642-CAAGGATT-A
• rs1555788144
• NM_006363.6:c.576_583delCAAGGATTinsA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006363.6(SEC23B):​c.576_583delCAAGGATTinsA​(p.Lys193fs) variant causes a frameshift, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC23B NM_006363.6 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.93
• Publications: 0 publications found

Genes affected

SEC23B (HGNC:10702): (SEC23 homolog B, COPII coat complex component) The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The function of this gene product has been implicated in cargo selection and concentration. Multiple alternatively spliced transcript variants have been identified in this gene. [provided by RefSeq, Feb 2010]

SEC23B Gene-Disease associations (from GenCC):

• congenital dyserythropoietic anemia type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, G2P
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 7

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• congenital dyserythropoietic anemia

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-18524642-CAAGGATT-A is Pathogenic according to our data. Variant chr20-18524642-CAAGGATT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 463383.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC23B	NM_006363.6	c.576_583delCAAGGATTinsA	p.Lys193fs	frameshift_variant, synonymous_variant	Exon 5 of 20	ENST00000650089.1	NP_006354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC23B	ENST00000650089.1	c.576_583delCAAGGATTinsA	p.Lys193fs	frameshift_variant, synonymous_variant	Exon 5 of 20		NM_006363.6	ENSP00000497473.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Pathogenic:1

Jul 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys193*) in the SEC23B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SEC23B-related disease. Loss-of-function variants in SEC23B are known to be pathogenic (PMID: 19561605, 25044164). For these reasons, this variant has been classified as Pathogenic. -

Congenital dyserythropoietic anemia, type II Pathogenic:1

Aug 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys193*) in the SEC23B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SEC23B-related disease. Loss-of-function variants in SEC23B are known to be pathogenic (PMID: 19561605, 25044164). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555788144; hg19: chr20-18505286;