14-91297376-G-T

Variant names:

• chr14-91297376-G-T
• rs142539336
• NM_001080414.4:c.3895C>A

Variant summary

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

The NM_001080414.4(CCDC88C):​c.3895C>A​(p.Arg1299Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,116 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1299C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.94
• 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 2 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	NM_001080414.4	MANE Select	c.3895C>A	p.Arg1299Ser	missense	Exon 22 of 30	NP_001073883.2
	CCDC88C	NR_189158.1		n.4025C>A		non_coding_transcript_exon	Exon 22 of 31
	CCDC88C	NR_189159.1		n.4025C>A		non_coding_transcript_exon	Exon 22 of 31

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.3895C>A	p.Arg1299Ser	missense	Exon 22 of 30	ENSP00000374507.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461116 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111678

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.15
Sift	Uncertain	0.011	D
Sift4G	Benign	0.079	T
Polyphen		0.97	D
Vest4		0.56
MutPred		0.34		Loss of MoRF binding (P = 0.0398)
MVP		0.73
MPC		0.16
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.32
Mutation Taster		=81/19	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: rs142539336; hg19: chr14-91763720;