rs45542736

Positions:

• chr14-91272764-C-G

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.5948G>C​(p.Gly1983Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,607,908 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (39 hom., cov: 32)
  • Exomes 𝑓: 0.017 (303 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.38

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=0.0019318163).
• BP6: Variant 14-91272764-C-G is Benign according to our data. Variant chr14-91272764-C-G is described in ClinVar as [Benign]. Clinvar id is 158116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0153 (2337/152334) while in subpopulation SAS AF= 0.0226 (109/4830). AF 95% confidence interval is 0.0191. There are 39 homozygotes in gnomad4. There are 1326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC88C	NM_001080414.4	c.5948G>C	p.Gly1983Ala	missense_variant	30/30	ENST00000389857.11	NP_001073883.2
CCDC88C	XM_011536796.3	c.5840G>C	p.Gly1947Ala	missense_variant	30/30		XP_011535098.1
CCDC88C	XM_047431418.1	c.5681G>C	p.Gly1894Ala	missense_variant	27/27		XP_047287374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11	c.5948G>C	p.Gly1983Ala	missense_variant	30/30	5	NM_001080414.4	ENSP00000374507.6
CCDC88C	ENST00000556726	c.*1782G>C		3_prime_UTR_variant	7/7	5		ENSP00000452406.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2340 AN: 152216 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0189 AC: 4534 AN: 240012 Hom.: 96 AF XY: 0.0198 AC XY: 2606 AN XY: 131408

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0226

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0172 AC: 25079 AN: 1455574 Hom.: 303 Cov.: 34 AF XY: 0.0174 AC XY: 12579 AN XY: 723968

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0332

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.0531

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0153 AC: 2337 AN: 152334 Hom.: 39 Cov.: 32 AF XY: 0.0178 AC XY: 1326 AN XY: 74484

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0702

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0154 Hom.: 13

Bravo AF: 0.0108

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00187 AC: 7

ESP6500EA AF: 0.0154 AC: 126

ExAC AF: 0.0179 AC: 2156

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 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	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.042
Sift	Benign	0.51	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.13	.;B
Vest4		0.018
MPC		0.16
ClinPred		0.0057	T
GERP RS		2.7
Varity_R		0.067
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: rs45542736; hg19: chr14-91739108;