rs1276747587

Variant names:

• chr14-91272631-A-C
• rs1276747587
• NM_001080414.4:c.6081T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-91272631-A-C
• chr14-91272631-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001080414.4(CCDC88C):​c.6081T>G​(p.Cys2027Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C2027C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.770
• Publications: 0 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinocerebellar ataxia type 40

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	NM_001080414.4	MANE Select	c.6081T>G	p.Cys2027Trp	missense	Exon 30 of 30	NP_001073883.2	Q9P219-1
	CCDC88C	NR_189158.1		n.6358T>G		non_coding_transcript_exon	Exon 31 of 31
	CCDC88C	NR_189159.1		n.6653T>G		non_coding_transcript_exon	Exon 31 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.6081T>G	p.Cys2027Trp	missense	Exon 30 of 30	ENSP00000374507.6	Q9P219-1
	CCDC88C	ENST00000556726.5	TSL:5	c.*1915T>G		3_prime_UTR	Exon 7 of 7	ENSP00000452406.1	H0YJX5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-0.77
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.59		Loss of disorder (P = 0.037)
MVP		0.59
MPC		0.70
ClinPred		0.99	D
GERP RS		-2.6
Varity_R		0.92
gMVP		0.62
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs1276747587; hg19: chr14-91738975;