NM_001354640.2:c.538G>T

Variant names:

• chr14-23103740-C-A
• rs1266315800
• NM_001354640.2:c.538G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001354640.2(CIROP):​c.538G>T​(p.Gly180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 550,714 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G180R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CIROP NM_001354640.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.538G>T	p.Gly180Trp	missense	Exon 4 of 16	NP_001341569.1	A0A1B0GTW7-1
	CIROP	NM_001402427.1		c.547G>T	p.Gly183Trp	missense	Exon 4 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.538G>T	p.Gly180Trp	missense	Exon 4 of 16	ENSP00000489869.1	A0A1B0GTW7-1
	CIROP	ENST00000644000.1		c.538G>T	p.Gly180Trp	missense	Exon 4 of 14	ENSP00000493582.1	A0A1B0GTW7-2
	CIROP	ENST00000642668.1		c.463G>T	p.Gly155Trp	missense	Exon 4 of 13	ENSP00000495729.1	A0A2R8Y752

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000182 AC: 1 AN: 550714 Hom.: 0 Cov.: 0 AF XY: 0.00000335 AC XY: 1 AN XY: 298134

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15808

American (AMR) AF: 0.00 AC: 0 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20030

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

South Asian (SAS) AF: 0.0000159 AC: 1 AN: 62776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 316968

Other (OTH) AF: 0.00 AC: 0 AN: 30606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T
MetaRNN	Uncertain	0.51	D
PhyloP100		2.8
GERP RS		4.8
Varity_R		0.34
gMVP		0.77

Splicing

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

Other links and lift over

dbSNP: rs1266315800; hg19: chr14-23572949;