rs78468999

Positions:

• chr14-91313938-C-G
• chr14-91313938-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080414.4(CCDC88C):​c.1878G>C​(p.Lys626Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,400 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K626K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.674

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01115182).
• BP6: Variant 14-91313938-C-G is Benign according to our data. Variant chr14-91313938-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.1878G>C	p.Lys626Asn	missense_variant	15/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.1878G>C	p.Lys626Asn	missense_variant	15/30	5	NM_001080414.4	P1
CCDC88C	ENST00000557507.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00113 AC: 281 AN: 248870 Hom.: 0 AF XY: 0.00115 AC XY: 156 AN XY: 135094

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00376

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00108 AC: 1577 AN: 1461314 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 769 AN XY: 726980

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.00421

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74354

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00472

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.49
MutPred		0.40		Loss of ubiquitination at K626 (P = 0.0074);
MVP		0.62
MPC		0.60
ClinPred		0.057	T
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.32
gMVP		0.25

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: rs78468999; hg19: chr14-91780282;