X-153592625-C-T

Position:

• chrX-153592625-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152274.5(CCNQ):​c.538G>A​(p.Gly180Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,824 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CCNQ NM_152274.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

CCNQ (HGNC:28434): (cyclin Q) Mutations in this gene have been shown to cause an X-linked dominant STAR syndrome that typically manifests syndactyly, telecanthus and anogenital and renal malformations. The protein encoded by this gene contains a cyclin-box-fold domain which suggests it may have a role in controlling nuclear cell division cycles. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCNQ	NM_152274.5	c.538G>A	p.Gly180Arg	missense_variant	4/5	ENST00000576892.8
CCNQ	NM_001130997.3	c.538G>A	p.Gly180Arg	missense_variant	4/5
CCNQ	XM_011531214.3	c.412G>A	p.Gly138Arg	missense_variant	4/5
CCNQ	XM_047442631.1	c.429+1922G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNQ	ENST00000576892.8	c.538G>A	p.Gly180Arg	missense_variant	4/5	1	NM_152274.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2017

The G180R variant in the FAM58A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G180R variant is not observed in large population cohorts (Lek et al., 2016). The G180R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G180R as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.050	T;D;.
Polyphen		0.99	D;D;.
Vest4		0.91
MutPred		0.62		Gain of MoRF binding (P = 0.0253);Gain of MoRF binding (P = 0.0253);.;
MVP		1.0
ClinPred		0.73	D
GERP RS		3.3
Varity_R		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557026069; hg19: chrX-152858083;