14-23101889-C-CA

Variant names:

• chr14-23101889-C-CA
• NM_001354640.2:c.1331dupT

Variant summary

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

The NM_001354640.2(CIROP):​c.1331dupT​(p.Leu444PhefsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CIROP NM_001354640.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.67

Genes affected

CIROP (HGNC:53647): (ciliated left-right organizer metallopeptidase) Predicted to enable peptidase activity. Predicted to be involved in cell adhesion and proteolysis. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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 14-23101889-C-CA is Pathogenic according to our data. Variant chr14-23101889-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1804116.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIROP	NM_001354640.2	c.1331dupT	p.Leu444PhefsTer51	frameshift_variant	Exon 11 of 16	ENST00000637218.2	NP_001341569.1
CIROP	NM_001402427.1	c.1166dupT	p.Leu389PhefsTer51	frameshift_variant	Exon 9 of 14		NP_001389356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIROP	ENST00000637218.2	c.1331dupT	p.Leu444PhefsTer51	frameshift_variant	Exon 11 of 16	5	NM_001354640.2	ENSP00000489869.1
CIROP	ENST00000644000.1	c.1157dupT	p.Leu386PhefsTer51	frameshift_variant	Exon 9 of 14			ENSP00000493582.1
CIROP	ENST00000642668.1	c.1082dupT	p.Leu361PhefsTer68	frameshift_variant	Exon 9 of 13			ENSP00000495729.1
CIROP	ENST00000644147.1	n.1088dupT		non_coding_transcript_exon_variant	Exon 8 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotaxy, visceral, 12, autosomal Pathogenic:1

Dec 12, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified together with NM_001354640.2:c.538G>C, p.(Gly180Arg) in the same patient. Criteria applied: PVS1, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23571098;