NM_001170754.2:c.1886G>C

Variant names:

• chr1-10948249-C-G
• rs530277951
• NM_001170754.2:c.1886G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170754.2(CIROZ):​c.1886G>C​(p.Gly629Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. G629V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CIROZ NM_001170754.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13778156).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIROZ	NM_001170754.2	MANE Select	c.1886G>C	p.Gly629Ala	missense	Exon 12 of 13	NP_001164225.1
	CIROZ	NM_001366227.2		c.1469G>C	p.Gly490Ala	missense	Exon 10 of 11	NP_001353156.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIROZ	ENST00000377004.9	TSL:5 MANE Select	c.1886G>C	p.Gly629Ala	missense	Exon 12 of 13	ENSP00000366203.4
	CIROZ	ENST00000520253.1	TSL:5	c.1739G>C	p.Gly580Ala	missense	Exon 11 of 12	ENSP00000429704.1	H0YBK5
	CIROZ	ENST00000418570.6	TSL:2	c.1388G>C	p.Gly463Ala	missense	Exon 7 of 8	ENSP00000387816.2	H3BM07

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461608 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.2
DANN	Uncertain	0.99
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.72
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.055
Sift	Uncertain	0.019	D
Sift4G	Benign	0.73	T
Vest4		0.089
MVP		0.095
MPC		0.19
ClinPred		0.22	T
GERP RS		0.15
PromoterAI		-0.027	Neutral
gMVP		0.059
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs530277951; hg19: chr1-11008306;