Genetic Variant CIROP:p.His664Gln (chr14-23100669-A-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001354640.2(CIROP):c.1992T>G(p.His664Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000724 in 399,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CIROP
NM_001354640.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.41

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:

C14orf119 (HGNC:20270): (chromosome 14 open reading frame 119) Located in cytosol and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

C14orf119 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012764394).

BP6

Variant 14-23100669-A-C is Benign according to our data. Variant chr14-23100669-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3054769.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00159 (242/152306) while in subpopulation AFR AF = 0.00549 (228/41552). AF 95% confidence interval is 0.0049. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIROP	NM_001354640.2	MANE Select	c.1992T>G	p.His664Gln	missense	Exon 15 of 16	NP_001341569.1	A0A1B0GTW7-1
CIROP	NM_001402427.1		c.1827T>G	p.His609Gln	missense	Exon 13 of 14	NP_001389356.1
C14orf119	NM_017924.4	MANE Select	c.*2588A>C		downstream_gene	N/A	NP_060394.1	Q9NWQ9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIROP	ENST00000637218.2	TSL:5 MANE Select	c.1992T>G	p.His664Gln	missense	Exon 15 of 16	ENSP00000489869.1	A0A1B0GTW7-1
CIROP	ENST00000644000.1		c.1818T>G	p.His606Gln	missense	Exon 13 of 14	ENSP00000493582.1	A0A1B0GTW7-2
CIROP	ENST00000642668.1		c.1470T>G	p.His490Gln	missense	Exon 12 of 13	ENSP00000495729.1	A0A2R8Y752

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000190

AC:

AN:

246826

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

125106

show subpopulations

African (AFR)

AF:

0.00474

AC:

AN:

7180

American (AMR)

AF:

0.000404

AC:

AN:

7434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9240

East Asian (EAS)

AF:

0.00

AC:

AN:

22894

South Asian (SAS)

AF:

0.00

AC:

AN:

3032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

158040

Other (OTH)

AF:

0.000611

AC:

AN:

16374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00159

AC:

242

AN:

152306

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00549

AC:

228

AN:

41552

American (AMR)

AF:

0.000784

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000693

Hom.:

Bravo

AF:

0.00174

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CIROP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.75

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.33

MetaRNN

Benign

0.013

PhyloP100

1.4

GERP RS

1.7

Varity_R

0.079

gMVP

0.063

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