rs1970911

chr14-91307150-G-Achr14-91307150-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080414.4(CCDC88C):c.3083C>T(p.Ala1028Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,634 control chromosomes in the GnomAD database, including 16,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A1028A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1510 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14986 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.348

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038718283).
• BP6: Variant 14-91307150-G-A is Benign according to our data. Variant chr14-91307150-G-A is described in ClinVar as [Benign]. Clinvar id is 158099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91307150-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.3083C>T	p.Ala1028Val	missense_variant	18/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.3083C>T	p.Ala1028Val	missense_variant	18/30	5	NM_001080414.4	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21196 AN: 152006 Hom.: 1509 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.160 AC: 39826 AN: 248940 Hom.: 3433 AF XY: 0.161 AC XY: 21801 AN XY: 135106

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.229

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.138 AC: 202394 AN: 1461508 Hom.: 14986 Cov.: 33 AF XY: 0.141 AC XY: 102607 AN XY: 727046

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.139 AC: 21218 AN: 152126 Hom.: 1510 Cov.: 32 AF XY: 0.146 AC XY: 10840 AN XY: 74370

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.146

Alfa AF: 0.134 Hom.: 2856

Bravo AF: 0.140

TwinsUK AF: 0.120 AC: 445

ALSPAC AF: 0.119 AC: 457

ESP6500AA AF: 0.112 AC: 430

ESP6500EA AF: 0.127 AC: 1051

ExAC AF: 0.159 AC: 19208

Asia WGS AF: 0.203 AC: 704 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.17
Dann	Benign	0.78
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.70	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.012
Sift	Benign	0.34	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.015
MPC		0.13
ClinPred		0.00058	T
GERP RS		-4.9
Varity_R		0.028
gMVP		0.12

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: rs1970911; hg19: chr14-91773494; COSMIC: COSV66236673;