14-91272702-C-G

Variant names:

• chr14-91272702-C-G
• rs370102360
• NM_001080414.4:c.6010G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001080414.4(CCDC88C):​c.6010G>C​(p.Val2004Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,611,380 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2004I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012060583).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC88C	NM_001080414.4	c.6010G>C	p.Val2004Leu	missense_variant	Exon 30 of 30	ENST00000389857.11	NP_001073883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11	c.6010G>C	p.Val2004Leu	missense_variant	Exon 30 of 30	5	NM_001080414.4	ENSP00000374507.6
CCDC88C	ENST00000556726	c.*1844G>C		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000452406.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000177 AC: 43 AN: 242496 Hom.: 0 AF XY: 0.000264 AC XY: 35 AN XY: 132768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000644

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1459028 Hom.: 2 Cov.: 29 AF XY: 0.000154 AC XY: 112 AN XY: 725858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.000191 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6010G>C (p.V2004L) alteration is located in exon 30 (coding exon 30) of the CCDC88C gene. This alteration results from a G to C substitution at nucleotide position 6010, causing the valine (V) at amino acid position 2004 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.3
DANN	Benign	0.51
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.27	.;N
REVEL	Benign	0.059
Sift	Benign	0.37	.;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0020	.;B
Vest4		0.033
MutPred		0.083		.;Gain of catalytic residue at V2004 (P = 0.0704);
MVP		0.16
MPC		0.13
ClinPred		0.0085	T
GERP RS		-0.27
Varity_R		0.046
gMVP		0.076

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

LitVar

Other links and lift over

dbSNP: rs370102360; hg19: chr14-91739046;