Genetic Variant CIROP:p.Arg22* (chr14-23104857-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_StrongPP5

The NM_001354640.2(CIROP):c.64C>T(p.Arg22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 700,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

CIROP
NM_001354640.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 0.461

Publications

0 publications found

Variant links:

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]

CIROP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

PP5

Variant 14-23104857-G-A is Pathogenic according to our data. Variant chr14-23104857-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2442172.

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.64C>T	p.Arg22*	stop_gained	Exon 1 of 16	NP_001341569.1	A0A1B0GTW7-1
	CIROP	NM_001402427.1		c.64C>T	p.Arg22*	stop_gained	Exon 1 of 14	NP_001389356.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIROP	ENST00000637218.2	TSL:5 MANE Select	c.64C>T	p.Arg22*	stop_gained	Exon 1 of 16	ENSP00000489869.1	A0A1B0GTW7-1
CIROP	ENST00000644000.1		c.64C>T	p.Arg22*	stop_gained	Exon 1 of 14	ENSP00000493582.1	A0A1B0GTW7-2
CIROP	ENST00000940842.1		c.64C>T	p.Arg22*	stop_gained	Exon 1 of 12	ENSP00000610901.1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

150958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000124

AC:

AN:

128582

AF XY:

0.000114

show subpopulations

Gnomad AFR exome

AF:

0.000157

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000192

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

AN:

549904

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

297606

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

15796

American (AMR)

AF:

0.000144

AC:

AN:

34644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19950

East Asian (EAS)

AF:

0.00

AC:

AN:

32096

South Asian (SAS)

AF:

0.0000319

AC:

AN:

62658

European-Finnish (FIN)

AF:

0.0000296

AC:

AN:

33796

Middle Eastern (MID)

AF:

0.000246

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.000183

AC:

AN:

316314

Other (OTH)

AF:

0.000163

AC:

AN:

30582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000132

AC:

AN:

151076

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73724

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41328

American (AMR)

AF:

0.000133

AC:

AN:

15016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67756

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000505

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 12, autosomal (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Pathogenic

(source)

DANN

Benign

0.71

FATHMM_MKL

Benign

0.085

PhyloP100

0.46

GERP RS

1.7

PromoterAI

0.017

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over