chr14-91272686-G-T

Variant names:

• chr14-91272686-G-T
• rs201940261
• NM_001080414.4:c.6026C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080414.4(CCDC88C):​c.6026C>A​(p.Pro2009Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P2009L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.42
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• spinocerebellar ataxia type 40

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41969994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC88C	NM_001080414.4	c.6026C>A	p.Pro2009Gln	missense_variant	Exon 30 of 30	ENST00000389857.11	NP_001073883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11	c.6026C>A	p.Pro2009Gln	missense_variant	Exon 30 of 30	5	NM_001080414.4	ENSP00000374507.6
CCDC88C	ENST00000556726.5	c.*1860C>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000452406.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459314 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726006

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111824

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	2.9	.;M
PhyloP100		9.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.7	.;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.51
MutPred		0.14		.;Loss of glycosylation at P2009 (P = 0.0179);
MVP		0.72
MPC		0.57
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.54
gMVP		0.44
Mutation Taster		=73/27	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: rs201940261; hg19: chr14-91739030;