rs115510695

chr14-91278091-C-Achr14-91278091-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001080414.4(CCDC88C):c.4889G>T(p.Arg1630Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1630H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.721

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 14-91278091-C-A is Benign according to our data. Variant chr14-91278091-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2049922.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.4889G>T	p.Arg1630Leu	missense_variant	29/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.4781G>T	p.Arg1594Leu	missense_variant	29/30
CCDC88C	XM_047431418.1	c.4622G>T	p.Arg1541Leu	missense_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.4889G>T	p.Arg1630Leu	missense_variant	29/30	5	NM_001080414.4	P1
CCDC88C	ENST00000334448.5	n.701G>T		non_coding_transcript_exon_variant	5/6	1
CCDC88C	ENST00000556726.5	c.*723G>T		3_prime_UTR_variant	6/7	5
CCDC88C	ENST00000557455.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460008 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 5 AN XY: 726214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The c.4889G>T (p.R1630L) alteration is located in exon 29 (coding exon 29) of the CCDC88C gene. This alteration results from a G to T substitution at nucleotide position 4889, causing the arginine (R) at amino acid position 1630 to be replaced by a leucine (L). The CCDC88C c.4889G>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.63	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.077
Sift	Benign	0.13	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.36	.;B
Vest4		0.53
MutPred		0.24		.;Loss of solvent accessibility (P = 0.0155);
MVP		0.61
MPC		0.22
ClinPred		0.56	D
GERP RS		3.4
Varity_R		0.098
gMVP		0.24

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: rs115510695; hg19: chr14-91744435; COSMIC: COSV105892224; COSMIC: COSV105892224;