rs201044013

chr14-91305920-C-Achr14-91305920-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080414.4(CCDC88C):c.3202G>T(p.Ala1068Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,180 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.54

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009902984).
• BP6: Variant 14-91305920-C-A is Benign according to our data. Variant chr14-91305920-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434622.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr14-91305920-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.3202G>T	p.Ala1068Ser	missense_variant	19/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.3202G>T	p.Ala1068Ser	missense_variant	19/30	5	NM_001080414.4	P1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152246 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00167 AC: 415 AN: 248396 Hom.: 2 AF XY: 0.00173 AC XY: 233 AN XY: 134852

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00996

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00239

Gnomad FIN exome AF: 0.0000947

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00207 AC: 3029 AN: 1460816 Hom.: 7 Cov.: 31 AF XY: 0.00205 AC XY: 1490 AN XY: 726670

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152364 Hom.: 2 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74506

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00228 AC: 19

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.049
Sift	Benign	0.12	T
Sift4G	Benign	0.33	T
Polyphen		0.12	B
Vest4		0.49
MVP		0.35
MPC		0.39
ClinPred		0.019	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201044013; hg19: chr14-91772264; COSMIC: COSV99062318;