rs941920

chr14-91272737-A-Gchr14-91272737-A-T

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.5975T>C(p.Leu1992Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,609,524 control chromosomes in the GnomAD database, including 629,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 ClinVar.

• Frequency:
  • Genomes: 𝑓 0.90 (61983 hom., cov: 34)
  • Exomes 𝑓: 0.88 (567818 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.254

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=9.007662E-7).
• BP6: Variant 14-91272737-A-G is Benign according to our data. Variant chr14-91272737-A-G is described in ClinVar as [Benign]. Clinvar id is 158118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91272737-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.5975T>C	p.Leu1992Pro	missense_variant	30/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.5867T>C	p.Leu1956Pro	missense_variant	30/30
CCDC88C	XM_047431418.1	c.5708T>C	p.Leu1903Pro	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.5975T>C	p.Leu1992Pro	missense_variant	30/30	5	NM_001080414.4	P1
CCDC88C	ENST00000556726.5	c.*1809T>C		3_prime_UTR_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136665 AN: 152166 Hom.: 61928 Cov.: 34

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.870

GnomAD3 exomes AF: 0.846 AC: 204013 AN: 241008 Hom.: 87667 AF XY: 0.844 AC XY: 111409 AN XY: 132042

Gnomad AFR exome AF: 0.981

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.861

Gnomad EAS exome AF: 0.575

Gnomad SAS exome AF: 0.751

Gnomad FIN exome AF: 0.947

Gnomad NFE exome AF: 0.896

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.880 AC: 1282470 AN: 1457240 Hom.: 567818 Cov.: 71 AF XY: 0.876 AC XY: 634881 AN XY: 724928

Gnomad4 AFR exome AF: 0.983

Gnomad4 AMR exome AF: 0.792

Gnomad4 ASJ exome AF: 0.863

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.944

Gnomad4 NFE exome AF: 0.899

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.898 AC: 136779 AN: 152284 Hom.: 61983 Cov.: 34 AF XY: 0.893 AC XY: 66512 AN XY: 74448

Gnomad4 AFR AF: 0.979

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.855

Gnomad4 EAS AF: 0.586

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.948

Gnomad4 NFE AF: 0.898

Gnomad4 OTH AF: 0.870

Alfa AF: 0.882 Hom.: 105414

Bravo AF: 0.894

TwinsUK AF: 0.894 AC: 3314

ALSPAC AF: 0.903 AC: 3480

ESP6500AA AF: 0.976 AC: 3605

ESP6500EA AF: 0.899 AC: 7322

ExAC AF: 0.851 AC: 102108

Asia WGS AF: 0.691 AC: 2406 AN: 3478

EpiCase AF: 0.884

EpiControl AF: 0.883

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2017	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.6
Dann	Benign	0.20
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.073	T;T
MetaRNN	Benign	9.0e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
REVEL	Benign	0.0060
Sift4G	Benign	0.32	T;T
Polyphen		0.0	.;B
Vest4		0.017
MPC		0.21
ClinPred		0.0022	T
GERP RS		-2.6
Varity_R		0.043
gMVP		0.069

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: rs941920; hg19: chr14-91739081;