14-91272702-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001080414.4(CCDC88C):c.6010G>A(p.Val2004Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,611,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V2004V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034694374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.6010G>A	p.Val2004Ile	missense_variant	30/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.5902G>A	p.Val1968Ile	missense_variant	30/30
CCDC88C	XM_047431418.1	c.5743G>A	p.Val1915Ile	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.6010G>A	p.Val2004Ile	missense_variant	30/30	5	NM_001080414.4	P1
CCDC88C	ENST00000556726.5	c.*1844G>A		3_prime_UTR_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 28 AN: 242496 Hom.: 0 AF XY: 0.0000753 AC XY: 10 AN XY: 132768

Gnomad AFR exome AF: 0.000204

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1459028 Hom.: 0 Cov.: 29 AF XY: 0.0000331 AC XY: 24 AN XY: 725858

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000124 AC: 15

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

Invitae

May 24, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2004 of the CCDC88C protein (p.Val2004Ile). This variant is present in population databases (rs370102360, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CCDC88C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	11
Dann	Benign	0.86
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
REVEL	Benign	0.10
Sift4G	Benign	0.28	T;T
Polyphen		0.045	.;B
Vest4		0.032
MVP		0.17
MPC		0.11
ClinPred		0.0068	T
GERP RS		-0.27
Varity_R		0.036
gMVP		0.068

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

Publications

LitVar

Other links and lift over

dbSNP: rs370102360; hg19: chr14-91739046; COSMIC: COSV57795777; COSMIC: COSV57795777;