chr14-91272677-GG-CT

Variant names:

• chr14-91272677-GG-CT
• NM_001080414.4:c.6034_6035delCCinsAG
• CCDC88C p.Pro2012Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001080414.4(CCDC88C):c.6034_6035delCCinsAG (p.Pro2012Arg) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: not found (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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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.6034_6035delCCinsAG p.Pro2012Arg	missense	N/A	Prot: NP_001073883.2 UniProt:
	CCDC88C NR_189158.1		n.6311_6312delCCinsAG	non_coding_transcript_exon	Exon 31 of 31	Prot:
	CCDC88C NR_189159.1		n.6606_6607delCCinsAG	non_coding_transcript_exon	Exon 31 of 31	Prot:

CCDC88C NM_001080414.4

MANE Select

HGVSc / HGVSpc.6034_6035delCCinsAGp.Pro2012Arg

Exon rankN/A

missense

Prot: NP_001073883.2UniProt: Q9P219-1

CCDC88C NR_189158.1

HGVSc / HGVSpn.6311_6312delCCinsAG

Exon rankExon 31 of 31

non_coding_transcript_exon

Prot:

CCDC88C NR_189159.1

HGVSc / HGVSpn.6606_6607delCCinsAG

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.6034_6035delCCinsAG p.Pro2012Arg	missense	N/A	Prot: ENSP00000374507.6 UniProt:
	CCDC88C ENST00000556726.5	TSL:5	c.*1868_*1869delCCinsAG	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000452406.1 UniProt:

CCDC88C ENST00000389857.11

TSL:5MANE Select

HGVSc / HGVSpc.6034_6035delCCinsAGp.Pro2012Arg

Exon rankN/A

missense

Prot: ENSP00000374507.6UniProt: Q9P219-1

CCDC88C ENST00000556726.5

TSL:5

HGVSc / HGVSpc.*1868_*1869delCCinsAG

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr14-91739021;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar