14-91272711-G-A

Variant names:

• chr14-91272711-G-A
• rs778199484
• NM_001080414.4:c.6001C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001080414.4(CCDC88C):​c.6001C>T​(p.Arg2001*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000617 in 1,458,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36
• Publications: 0 publications found

Genes affected

CCDC88C (HGNC:19967): (coiled-coil domain containing 88C) This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the Wnt signalling pathway. The protein encoded by this gene has a PDZ-domain binding motif in its C-terminus with which it interacts with the dishevelled protein. Dishevelled is a scaffold protein involved in the regulation of the Wnt signaling pathway. The Wnt signaling pathway plays an important role in embryonic development, tissue maintenance, and cancer progression. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain. [provided by RefSeq, Jan 2013]

CCDC88C Gene-Disease associations (from GenCC):

• hydrocephalus, nonsyndromic, autosomal recessive 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• spinocerebellar ataxia type 40

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0141 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080414.4. 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
	CCDC88C	NM_001080414.4	MANE Select	c.6001C>T	p.Arg2001*	stop_gained	Exon 30 of 30	NP_001073883.2	Q9P219-1
	CCDC88C	NR_189158.1		n.6278C>T		non_coding_transcript_exon	Exon 31 of 31
	CCDC88C	NR_189159.1		n.6573C>T		non_coding_transcript_exon	Exon 31 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.6001C>T	p.Arg2001*	stop_gained	Exon 30 of 30	ENSP00000374507.6	Q9P219-1
	CCDC88C	ENST00000556726.5	TSL:5	c.*1835C>T		3_prime_UTR	Exon 7 of 7	ENSP00000452406.1	H0YJX5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458846 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725776

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111712

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.32	N
PhyloP100		4.4
Vest4		0.093
GERP RS		4.0
Mutation Taster		=19/181	disease causing

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: rs778199484; hg19: chr14-91739055; COSMIC: COSV57797524; COSMIC: COSV57797524;