1-10949622-G-C

Variant names:

• chr1-10949622-G-C
• rs1281013
• NM_001170754.2:c.1290+2C>G

Variant summary

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

The NM_001170754.2(CIROZ):​c.1290+2C>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CIROZ NM_001170754.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 0 publications found

Genes affected

CIROZ (HGNC:26730): (chromosome 1 open reading frame 127) Predicted to be involved in heart development. Predicted to act upstream of or within determination of left/right symmetry. [provided by Alliance of Genome Resources, Apr 2022]

CIROZ Gene-Disease associations (from GenCC):

• visceral heterotaxy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170754.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIROZ	NM_001170754.2	MANE Select	c.1290+2C>G		splice_donor intron	N/A	NP_001164225.1
	CIROZ	NM_001366227.2		c.873+2C>G		splice_donor intron	N/A	NP_001353156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf127	ENST00000377004.9	TSL:5 MANE Select	c.1290+2C>G		splice_donor intron	N/A	ENSP00000366203.4
	C1orf127	ENST00000476357.1	TSL:2	n.130C>G		non_coding_transcript_exon	Exon 1 of 2
	C1orf127	ENST00000520253.1	TSL:5	c.1143+80C>G		intron	N/A	ENSP00000429704.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447168 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718474

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4880

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105650

Other (OTH) AF: 0.00 AC: 0 AN: 59792

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.7
DANN	Benign	0.40
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.024	N
PhyloP100		0.12
GERP RS		-0.58
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1281013; hg19: chr1-11009679;