rs142539336

Positions:

chr14-91297376-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.94

Variant links:

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 links:

CCDC88C (HGNC:):

CCDC88C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=3, 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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC88C	NM_001080414.4 linkuse as main transcript	c.3895C>T	p.Arg1299Cys	missense_variant	22/30	ENST00000389857.11	NP_001073883.2	Q9P219-1B4DZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11 linkuse as main transcript	c.3895C>T	p.Arg1299Cys	missense_variant	22/30	5	NM_001080414.4	ENSP00000374507.6		Q9P219-1

Frequencies

GnomAD3 genomes

AF:

0.00426

AC:

649

AN:

152222

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00469

AC XY:

630

AN XY:

134466

show subpopulations

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.:

Cov.:

AF XY:

0.00686

AC XY:

4988

AN XY:

726742

show subpopulations

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.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00725

AC:

ExAC

AF:

0.00449

AC:

544

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00647

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CCDC88C: BP4, BS2 -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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. -

CCDC88C-related disorder

Benign:1

Likely benign, no assertion criteria provided

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.026

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.60

MVP

0.67

MPC

0.55

ClinPred

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over