rs63749972

Variant names:

• chrX-153588455-C-T
• rs63749972
• NM_152274.5:c.658-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_152274.5(CCNQ):​c.658-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: CCNQ NM_152274.5 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.92
• Publications: 0 publications found

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]

CCNQ Gene-Disease associations (from GenCC):

• syndactyly-telecanthus-anogenital and renal malformations syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153588455-C-T is Pathogenic according to our data. Variant chrX-153588455-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10675.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152274.5. 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
	CCNQ	NM_152274.5	MANE Select	c.658-1G>A		splice_acceptor intron	N/A	NP_689487.2	Q8N1B3-1
	CCNQ	NM_001130997.3		c.658-61G>A		intron	N/A	NP_001124469.1	Q8N1B3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNQ	ENST00000576892.8	TSL:1 MANE Select	c.658-1G>A		splice_acceptor intron	N/A	ENSP00000461135.1	Q8N1B3-1
	CCNQ	ENST00000875308.1		c.646-1G>A		splice_acceptor intron	N/A	ENSP00000545367.1
	CCNQ	ENST00000919978.1		c.628-1G>A		splice_acceptor intron	N/A	ENSP00000590037.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Syndactyly-telecanthus-anogenital and renal malformations syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.9
GERP RS		4.4

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: rs63749972; hg19: chrX-152853913;