Genetic Variant CCDC88C:p.Arg1659Arg (chr14-91278005-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001080414.4(CCDC88C):c.4975C>A(p.Arg1659Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,582,112 control chromosomes in the GnomAD database, including 1,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 68 hom., cov: 32)

Exomes 𝑓: 0.034 ( 957 hom. )

Consequence

CCDC88C
NM_001080414.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.00

Publications

4 publications found

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 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

CCDC88C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 14-91278005-G-T is Benign according to our data. Variant chr14-91278005-G-T is described in ClinVar as Benign. ClinVar VariationId is 158114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0254 (3871/152328) while in subpopulation NFE AF = 0.0377 (2562/68028). AF 95% confidence interval is 0.0364. There are 68 homozygotes in GnomAd4. There are 1815 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 68 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC88C	NM_001080414.4	MANE Select	c.4975C>A	p.Arg1659Arg	synonymous	Exon 29 of 30	NP_001073883.2
CCDC88C	NR_189158.1		n.5252C>A		non_coding_transcript_exon	Exon 30 of 31
CCDC88C	NR_189159.1		n.5547C>A		non_coding_transcript_exon	Exon 30 of 31

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.4975C>A	p.Arg1659Arg	synonymous	Exon 29 of 30	ENSP00000374507.6
CCDC88C	ENST00000334448.5	TSL:1	n.787C>A		non_coding_transcript_exon	Exon 5 of 6
CCDC88C	ENST00000556726.5	TSL:5	c.*809C>A		3_prime_UTR	Exon 6 of 7	ENSP00000452406.1

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3869

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00782

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0267

AC:

5341

AN:

200208

AF XY:

0.0271

show subpopulations

Gnomad AFR exome

AF:

0.00772

Gnomad AMR exome

AF:

0.0212

Gnomad ASJ exome

AF:

0.0475

Gnomad EAS exome

AF:

0.000139

Gnomad FIN exome

AF:

0.0169

Gnomad NFE exome

AF:

0.0383

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0342

AC:

48841

AN:

1429784

Hom.:

957

Cov.:

AF XY:

0.0339

AC XY:

24031

AN XY:

708036

show subpopulations

African (AFR)

AF:

0.00794

AC:

260

AN:

32752

American (AMR)

AF:

0.0223

AC:

899

AN:

40252

Ashkenazi Jewish (ASJ)

AF:

0.0509

AC:

1300

AN:

25534

East Asian (EAS)

AF:

0.0000528

AC:

AN:

37850

South Asian (SAS)

AF:

0.0153

AC:

1259

AN:

82316

European-Finnish (FIN)

AF:

0.0179

AC:

915

AN:

51156

Middle Eastern (MID)

AF:

0.0489

AC:

279

AN:

5710

European-Non Finnish (NFE)

AF:

0.0382

AC:

41887

AN:

1095160

Other (OTH)

AF:

0.0345

AC:

2040

AN:

59054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

2982

5963

8945

11926

14908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1560

3120

4680

6240

7800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0254

AC:

3871

AN:

152328

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1815

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00779

AC:

324

AN:

41570

American (AMR)

AF:

0.0297

AC:

454

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

159

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0176

AC:

187

AN:

10620

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0377

AC:

2562

AN:

68028

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0283

Hom.:

Bravo

AF:

0.0267

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Apr 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Spinocerebellar ataxia type 40

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hydrocephalus, nonsyndromic, autosomal recessive 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.7

(source)

DANN

Benign

0.58

PhyloP100

3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over