rs61745576

Positions:

• chr14-91339333-G-C

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.754C>G​(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,613,790 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (11 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.04

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=0.0098232925).
• BP6: Variant 14-91339333-G-C is Benign according to our data. Variant chr14-91339333-G-C is described in ClinVar as [Benign]. Clinvar id is 158121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91339333-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00557 (849/152372) while in subpopulation AFR AF= 0.0197 (818/41588). AF 95% confidence interval is 0.0186. There are 5 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC88C	NM_001080414.4	c.754C>G	p.Leu252Val	missense_variant	8/30	ENST00000389857.11	NP_001073883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC88C	ENST00000389857.11	c.754C>G	p.Leu252Val	missense_variant	8/30	5	NM_001080414.4	ENSP00000374507.6
CCDC88C	ENST00000554872.5	n.694C>G		non_coding_transcript_exon_variant	7/7	4

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 847 AN: 152254 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00126 AC: 313 AN: 247632 Hom.: 1 AF XY: 0.000936 AC XY: 126 AN XY: 134608

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000521 AC: 762 AN: 1461418 Hom.: 11 Cov.: 31 AF XY: 0.000461 AC XY: 335 AN XY: 726982

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.00557 AC: 849 AN: 152372 Hom.: 5 Cov.: 33 AF XY: 0.00531 AC XY: 396 AN XY: 74518

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00618

ESP6500AA AF: 0.0203 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	0.28
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.061	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.56
MVP		0.71
MPC		0.57
ClinPred		0.056	T
GERP RS		2.4
Varity_R		0.13
gMVP		0.35

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: rs61745576; hg19: chr14-91805677;