14-91307224-T-C

Position:

• chr14-91307224-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080414.4(CCDC88C):​c.3009A>G​(p.Leu1003Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,612,236 control chromosomes in the GnomAD database, including 260,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23643 hom., cov: 32)
  • Exomes 𝑓: 0.57 (237164 hom.)
• Consequence: CCDC88C NM_001080414.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0160

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-91307224-T-C is Benign according to our data. Variant chr14-91307224-T-C is described in ClinVar as [Benign]. Clinvar id is 158098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91307224-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.016 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC88C	NM_001080414.4	c.3009A>G	p.Leu1003Leu	splice_region_variant, synonymous_variant	18/30	ENST00000389857.11	NP_001073883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11	c.3009A>G	p.Leu1003Leu	splice_region_variant, synonymous_variant	18/30	5	NM_001080414.4	ENSP00000374507.6

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84312 AN: 151984 Hom.: 23633 Cov.: 32

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.532 AC: 132116 AN: 248246 Hom.: 36192 AF XY: 0.526 AC XY: 70862 AN XY: 134842

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.508

Gnomad EAS exome AF: 0.367

Gnomad SAS exome AF: 0.388

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.584

Gnomad OTH exome AF: 0.550

GnomAD4 exome AF: 0.566 AC: 826433 AN: 1460134 Hom.: 237164 Cov.: 42 AF XY: 0.560 AC XY: 406632 AN XY: 726404

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.544

GnomAD4 genome AF: 0.555 AC: 84369 AN: 152102 Hom.: 23643 Cov.: 32 AF XY: 0.549 AC XY: 40805 AN XY: 74338

Gnomad4 AFR AF: 0.548

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.390

Gnomad4 FIN AF: 0.633

Gnomad4 NFE AF: 0.588

Gnomad4 OTH AF: 0.520

Alfa AF: 0.565 Hom.: 29721

Bravo AF: 0.545

Asia WGS AF: 0.399 AC: 1393 AN: 3478

EpiCase AF: 0.567

EpiControl AF: 0.565

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

Spinocerebellar ataxia type 40 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hydrocephalus, nonsyndromic, autosomal recessive 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.0
DANN	Benign	0.36

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: rs1970912; hg19: chr14-91773568; COSMIC: COSV66237429;