NM_001354640.2:c.92C>T

Variant names:

• chr14-23104829-G-A
• rs553352307
• NM_001354640.2:c.92C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_001354640.2(CIROP):​c.92C>T​(p.Ser31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 702,970 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: CIROP NM_001354640.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 2.27
• 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: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 14-23104829-G-A is Pathogenic according to our data. Variant chr14-23104829-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1335920.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009967804). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (161/152220) while in subpopulation NFE AF = 0.00197 (134/68016). AF 95% confidence interval is 0.0017. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.92C>T	p.Ser31Phe	missense	Exon 1 of 16	NP_001341569.1	A0A1B0GTW7-1
	CIROP	NM_001402427.1		c.92C>T	p.Ser31Phe	missense	Exon 1 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.92C>T	p.Ser31Phe	missense	Exon 1 of 16	ENSP00000489869.1	A0A1B0GTW7-1
	CIROP	ENST00000644000.1		c.92C>T	p.Ser31Phe	missense	Exon 1 of 14	ENSP00000493582.1	A0A1B0GTW7-2
	CIROP	ENST00000642668.1		c.17C>T	p.Ser6Phe	missense	Exon 1 of 13	ENSP00000495729.1	A0A2R8Y752

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 162 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00120 AC: 162 AN: 134452 AF XY: 0.00122

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.000572

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00135 AC: 746 AN: 550750 Hom.: 2 Cov.: 0 AF XY: 0.00132 AC XY: 394 AN XY: 298154

African (AFR) AF: 0.000696 AC: 11 AN: 15808

American (AMR) AF: 0.000518 AC: 18 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.000100 AC: 2 AN: 20006

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.00104 AC: 65 AN: 62760

European-Finnish (FIN) AF: 0.0000297 AC: 1 AN: 33702

Middle Eastern (MID) AF: 0.00147 AC: 6 AN: 4076

European-Non Finnish (NFE) AF: 0.00189 AC: 598 AN: 316950

Other (OTH) AF: 0.00147 AC: 45 AN: 30628

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74422

African (AFR) AF: 0.000289 AC: 12 AN: 41516

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 68016

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00126

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ExAC AF: 0.000519 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Heterotaxy, visceral, 12, autosomal (2)
-	-	1	CIROP-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.82
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.010	T
PhyloP100		2.3
GERP RS		5.5
PromoterAI		-0.013	Neutral
Varity_R		0.28
gMVP		0.25

Splicing

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

Other links and lift over

dbSNP: rs553352307; hg19: chr14-23574038;