14-91272677-G-C

Variant names:

• chr14-91272677-G-C
• rs771028975
• NM_001080414.4:c.6035C>G
• CCDC88C p.Pro2012Arg

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 (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_001080414.4(CCDC88C):c.6035C>G (p.Pro2012Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,192 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P2012L: Uncertain_significance (ClinVar VariationId 1342715, 2 stars); p.P2012= (synonymous): Likely_benign (ClinVar VariationId 2906785, 1 star)

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.

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>G p.Pro2012Arg	missense	Exon 30 of 30	Prot: NP_001073883.2 UniProt:
	CCDC88C NR_189158.1		n.6312C>G	non_coding_transcript_exon	Exon 31 of 31	Prot:
	CCDC88C NR_189159.1		n.6607C>G	non_coding_transcript_exon	Exon 31 of 31	Prot:

CCDC88C NM_001080414.4

MANE Select

HGVSc / HGVSpc.6035C>Gp.Pro2012Arg

Exon rankExon 30 of 30

missense

Prot: NP_001073883.2UniProt: Q9P219-1

CCDC88C NR_189158.1

HGVSc / HGVSpn.6312C>G

Exon rankExon 31 of 31

non_coding_transcript_exon

Prot:

CCDC88C NR_189159.1

HGVSc / HGVSpn.6607C>G

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>G p.Pro2012Arg	missense	Exon 30 of 30	Prot: ENSP00000374507.6 UniProt:
	CCDC88C ENST00000556726.5	TSL:5	c.*1869C>G	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000452406.1 UniProt:

CCDC88C ENST00000389857.11

TSL:5MANE Select

HGVSc / HGVSpc.6035C>Gp.Pro2012Arg

Exon rankExon 30 of 30

missense

Prot: ENSP00000374507.6UniProt: Q9P219-1

CCDC88C ENST00000556726.5

TSL:5

HGVSc / HGVSpc.*1869C>G

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152192	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:29
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152192	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:47196	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Benign	0.29
GPN-Star LLR	N/A	-6.9
GPN-Star score	N/A	6.9
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.40	T
Mutation Taster	N/A	68/32	polymorphism
MutationAssessor	Pathogenic	2.9	M
PhyloP100	Pathogenic	9.4
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Varity_R	N/A	0.28
VESM-3B	Benign	-4.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar