rs139544500

Positions:

• chr14-91281488-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080414.4(CCDC88C):​c.4668G>A​(p.Leu1556=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,613,946 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (53 hom.)
• Consequence: CCDC88C NM_001080414.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.134

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-91281488-C-T is Benign according to our data. Variant chr14-91281488-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 447020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91281488-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00489 (745/152306) while in subpopulation AMR AF= 0.00725 (111/15300). AF 95% confidence interval is 0.00656. There are 3 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.4668G>A	p.Leu1556=	synonymous_variant	27/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.4560G>A	p.Leu1520=	synonymous_variant	27/30
CCDC88C	XM_047431418.1	c.4401G>A	p.Leu1467=	synonymous_variant	24/27
CCDC88C	XM_047431419.1	c.4668G>A	p.Leu1556=	synonymous_variant	27/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.4668G>A	p.Leu1556=	synonymous_variant	27/30	5	NM_001080414.4	P1
CCDC88C	ENST00000334448.5	n.333G>A		non_coding_transcript_exon_variant	2/6	1
CCDC88C	ENST00000556726.5	c.*502G>A		3_prime_UTR_variant	4/7	5

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 747 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00563 AC: 1403 AN: 249274 Hom.: 10 AF XY: 0.00551 AC XY: 745 AN XY: 135226

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00701

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00875

GnomAD4 exome AF: 0.00767 AC: 11205 AN: 1461640 Hom.: 53 Cov.: 31 AF XY: 0.00738 AC XY: 5368 AN XY: 727108

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00787

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74474

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00682 Hom.: 2

Bravo AF: 0.00578

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.0101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CCDC88C: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 03, 2016

- -

Hydrocephalus, nonsyndromic, autosomal recessive 1;C4518336:Spinocerebellar ataxia type 40 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.1
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139544500; hg19: chr14-91747832; COSMIC: COSV57796003; COSMIC: COSV57796003;