rs142539336

chr14-91297376-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001080414.4(CCDC88C):c.3895C>T(p.Arg1299Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00666 in 1,613,446 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (44 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.94

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010968417).
• BP6: Variant 14-91297376-G-A is Benign according to our data. Variant chr14-91297376-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376774.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00426 (649/152340) while in subpopulation NFE AF= 0.00726 (494/68030). AF 95% confidence interval is 0.00673. There are 1 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.3895C>T	p.Arg1299Cys	missense_variant	22/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.3895C>T	p.Arg1299Cys	missense_variant	22/30	5	NM_001080414.4	P1

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 649 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00442 AC: 1095 AN: 247678 Hom.: 8 AF XY: 0.00469 AC XY: 630 AN XY: 134466

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.00418

Gnomad SAS exome AF: 0.00191

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00692 AC: 10104 AN: 1461106 Hom.: 44 Cov.: 33 AF XY: 0.00686 AC XY: 4988 AN XY: 726742

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.00491

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.00274

Gnomad4 NFE exome AF: 0.00806

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74488

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00726

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00612 Hom.: 8

Bravo AF: 0.00436

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.00725 AC: 62

ExAC AF: 0.00449 AC: 544

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00647

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CCDC88C: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

CCDC88C-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2022

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	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.67
MPC		0.55
ClinPred		0.030	T
GERP RS		5.3
Varity_R		0.52
gMVP		0.27

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: rs142539336; hg19: chr14-91763720; COSMIC: COSV66235587;