CCDC88C p.Pro2012Leu

Variant names:

• chr14-91272677-G-A
• rs771028975
• NM_001080414.4:c.6035C>T
• CCDC88C p.Pro2012Leu

Your query was ambiguous. Multiple possible variants found:

• chr14-91272677-G-A
• chr14-91272676-CG-AA
• chr14-91272676-CG-GA
• chr14-91272676-CG-TA
• chr14-91272677-GG-AA
• chr14-91272676-CGG-TAA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_001080414.4(CCDC88C):c.6035C>T (p.Pro2012Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The gene CCDC88C is a tumor suppressor gene (CancerMine: 2 TSG citations). The variant allele was found at a cumulative frequency of 0.0000174 (AC=28) in the gnomAD database across 1,611,428 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00003. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.42). Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P2012= (synonymous): Likely_benign (ClinVar VariationId 2906785, 1 star) The variant has been observed in cBioPortal in 2 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.42
• Publications: 0 publications found

Genes affected

CCDC88C (HGNC:19967): (coiled-coil and HOOK domain protein 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• spinocerebellar ataxia type 40

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000030 — very rare (O3 supporting [+1])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001080414.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CCDC88C NM_001080414.4	MANE Select	c.6035C>T p.Pro2012Leu	missense	Exon 30 of 30	Prot: NP_001073883.2 UniProt:
	CCDC88C NR_189158.1		n.6312C>T	non_coding_transcript_exon	Exon 31 of 31	Prot:
	CCDC88C NR_189159.1		n.6607C>T	non_coding_transcript_exon	Exon 31 of 31	Prot:

CCDC88C NM_001080414.4

MANE Select

HGVSc / HGVSpc.6035C>Tp.Pro2012Leu

Exon rankExon 30 of 30

missense

Prot: NP_001073883.2UniProt: Q9P219-1

CCDC88C NR_189158.1

HGVSc / HGVSpn.6312C>T

Exon rankExon 31 of 31

non_coding_transcript_exon

Prot:

CCDC88C NR_189159.1

HGVSc / HGVSpn.6607C>T

Exon rankExon 31 of 31

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CCDC88C ENST00000389857.11	TSL:5MANE Select	c.6035C>T p.Pro2012Leu	missense	Exon 30 of 30	Prot: ENSP00000374507.6 UniProt:
	CCDC88C ENST00000556726.5	TSL:5	c.*1869C>T	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000452406.1 UniProt:

CCDC88C ENST00000389857.11

TSL:5MANE Select

HGVSc / HGVSpc.6035C>Tp.Pro2012Leu

Exon rankExon 30 of 30

missense

Prot: ENSP00000374507.6UniProt: Q9P219-1

CCDC88C ENST00000556726.5

TSL:5

HGVSc / HGVSpc.*1869C>T

Exon rankExon 7 of 7

3_prime_UTR

Prot: ENSP00000452406.1UniProt: H0YJX5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152192	Cov:33
GnomAD2 exomes	AF: 0.0000413	AC:10	Hom:	AN:242324	Cov:
GnomAD4 exome	AF: 0.0000164	AC:24	Hom:0	AN:1459236	Cov:29
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152192	Cov:33
TOPMed (Bravo)	AF: 0.0000416	AC:11	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000636	AC:3	Hom:0	AN:47196	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122416	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000354	4	113090	0.0000420	8	190470

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	CCDC88C-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Spinocerebellar ataxia type 40 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Benign	0.075
GPN-Star LLR	N/A	-6.4
GPN-Star score	N/A	6.4
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.40	T
Mutation Taster	N/A	78/22	polymorphism
MutationAssessor	Pathogenic	2.9	M
PhyloP100	Pathogenic	9.4
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.068	T
Sift4G	Uncertain	0.0080	D
Varity_R	N/A	0.15
VESM-3B	Benign	-4.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs771028975;

hg19: chr14-91739021;

COSMIC: COSV105892220;

COSMIC: COSV105892220;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar