rs1555788144

Positions:

• chr20-18524641-CCAAGGATT-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006363.6(SEC23B):​c.576_583delinsA​(p.Lys193Ter) variant causes a frameshift 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 463383.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23B	NM_006363.6	c.576_583delinsA	p.Lys193Ter	frameshift_variant	5/20	ENST00000650089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23B	ENST00000650089.1	c.576_583delinsA	p.Lys193Ter	frameshift_variant	5/20		NM_006363.6	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SEC23B are known to be pathogenic (PMID: 19561605, 25044164). This variant has not been reported in the literature in individuals with SEC23B-related disease. This variant is not present in population databases (ExAC no frequency). 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. -

Congenital dyserythropoietic anemia, type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2017

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555788144; hg19: chr20-18505286;