Genetic Variant NM_001080414.4:c.5251G>T (chr14-91273461-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080414.4(CCDC88C):c.5251G>T(p.Val1751Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000488 in 1,435,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1751I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CCDC88C
NM_001080414.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.52

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18026122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC88C	NM_001080414.4 link	c.5251G>T	p.Val1751Leu	missense_variant	Exon 30 of 30	ENST00000389857.11	NP_001073883.2	Q9P219-1B4DZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC88C	ENST00000389857.11 link	c.5251G>T	p.Val1751Leu	missense_variant	Exon 30 of 30	5	NM_001080414.4	ENSP00000374507.6	Q9P219-1
CCDC88C	ENST00000556726.5 link	c.*1085G>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000452406.1	H0YJX5
CCDC88C	ENST00000334448.5 link	n.*8G>T		downstream_gene_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

228104

AF XY:

0.00000802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000488

AC:

AN:

1435214

Hom.:

Cov.:

AF XY:

0.00000703

AC XY:

AN XY:

711718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32184

American (AMR)

AF:

0.00

AC:

AN:

40792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.00

AC:

AN:

38834

South Asian (SAS)

AF:

0.0000723

AC:

AN:

83040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097926

Other (OTH)

AF:

0.0000169

AC:

AN:

59018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

T;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

4.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0090

D;T

Sift4G

Benign

0.47

T;T

Polyphen

0.33

.;B

Vest4

0.75

MutPred

0.20

.;Loss of methylation at K1752 (P = 0.0413);

MVP

0.65

MPC

0.17

ClinPred

0.68

GERP RS

4.9

Varity_R

0.078

gMVP

0.22

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over