14-23102440-C-T

Variant names:

• chr14-23102440-C-T
• NM_001354640.2:c.1038G>A
• CIROP p.Trp346*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001354640.2(CIROP):​c.1038G>A​(p.Trp346*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CIROP NM_001354640.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354640.2. 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
	CIROP	NM_001354640.2	MANE Select	c.1038G>A	p.Trp346*	stop_gained	Exon 9 of 16	NP_001341569.1	A0A1B0GTW7-1
	CIROP	NM_001402427.1		c.873G>A	p.Trp291*	stop_gained	Exon 7 of 14	NP_001389356.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIROP	ENST00000637218.2	TSL:5 MANE Select	c.1038G>A	p.Trp346*	stop_gained	Exon 9 of 16	ENSP00000489869.1	A0A1B0GTW7-1
	CIROP	ENST00000644000.1		c.864G>A	p.Trp288*	stop_gained	Exon 7 of 14	ENSP00000493582.1	A0A1B0GTW7-2
	CIROP	ENST00000642668.1		c.789G>A	p.Trp263*	stop_gained	Exon 7 of 13	ENSP00000495729.1	A0A2R8Y752

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	39
DANN	Benign	0.72
FATHMM_MKL	Benign	0.74	D
PhyloP100		3.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-23571649;