rs17127223

Positions:

• chr14-91313384-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080414.4(CCDC88C):​c.2432C>A​(p.Ala811Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,609,168 control chromosomes in the GnomAD database, including 90 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.

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.106

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=0.0020397007).
• BP6: Variant 14-91313384-G-T is Benign according to our data. Variant chr14-91313384-G-T is described in ClinVar as [Benign]. Clinvar id is 158096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2183/152228) while in subpopulation AFR AF= 0.0495 (2057/41522). AF 95% confidence interval is 0.0478. There are 44 homozygotes in gnomad4. There are 1023 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.2432C>A	p.Ala811Glu	missense_variant	15/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.2432C>A	p.Ala811Glu	missense_variant	15/30	5	NM_001080414.4	P1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2159 AN: 152110 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00372 AC: 903 AN: 242954 Hom.: 25 AF XY: 0.00292 AC XY: 387 AN XY: 132576

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00147 AC: 2147 AN: 1456940 Hom.: 46 Cov.: 32 AF XY: 0.00127 AC XY: 918 AN XY: 725012

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.0143 AC: 2183 AN: 152228 Hom.: 44 Cov.: 32 AF XY: 0.0137 AC XY: 1023 AN XY: 74444

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00147 Hom.: 8

Bravo AF: 0.0165

ESP6500AA AF: 0.0537 AC: 221

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00446 AC: 539

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000594

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	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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	0.092
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.9
DANN	Benign	0.70
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.074
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.37	T
Polyphen		0.021	B
Vest4		0.14
MVP		0.25
MPC		0.16
ClinPred		0.0067	T
GERP RS		-5.7
Varity_R		0.10
gMVP		0.15

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: rs17127223; hg19: chr14-91779728;