rs45560241

Variant names:

• chr14-91272732-G-C
• rs45560241
• NM_001080414.4:c.5980C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-91272732-G-C
• chr14-91272732-G-T
• chr14-91272732-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080414.4(CCDC88C):​c.5980C>G​(p.Arg1994Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,610,252 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1994L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (56 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.51
• Publications: 4 publications found

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]

CCDC88C Gene-Disease associations (from GenCC):

• hydrocephalus, nonsyndromic, autosomal recessive 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• spinocerebellar ataxia type 40

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035588741).
• BP6: Variant 14-91272732-G-C is Benign according to our data. Variant chr14-91272732-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00589 (897/152336) while in subpopulation NFE AF = 0.00736 (501/68034). AF 95% confidence interval is 0.00683. There are 8 homozygotes in GnomAd4. There are 478 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	NM_001080414.4	MANE Select	c.5980C>G	p.Arg1994Gly	missense	Exon 30 of 30	NP_001073883.2	Q9P219-1
	CCDC88C	NR_189158.1		n.6257C>G		non_coding_transcript_exon	Exon 31 of 31
	CCDC88C	NR_189159.1		n.6552C>G		non_coding_transcript_exon	Exon 31 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.5980C>G	p.Arg1994Gly	missense	Exon 30 of 30	ENSP00000374507.6	Q9P219-1
	CCDC88C	ENST00000556726.5	TSL:5	c.*1814C>G		3_prime_UTR	Exon 7 of 7	ENSP00000452406.1	H0YJX5

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 896 AN: 152218 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00649 AC: 1560 AN: 240498 AF XY: 0.00641

Gnomad AFR exome AF: 0.000482

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.00876

Gnomad OTH exome AF: 0.00692

GnomAD4 exome AF: 0.00718 AC: 10461 AN: 1457916 Hom.: 56 Cov.: 29 AF XY: 0.00694 AC XY: 5031 AN XY: 725304

African (AFR) AF: 0.000897 AC: 30 AN: 33462

American (AMR) AF: 0.00244 AC: 109 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 113 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000627 AC: 54 AN: 86142

European-Finnish (FIN) AF: 0.0217 AC: 1094 AN: 50442

Middle Eastern (MID) AF: 0.000880 AC: 5 AN: 5684

European-Non Finnish (NFE) AF: 0.00783 AC: 8705 AN: 1111460

Other (OTH) AF: 0.00581 AC: 350 AN: 60284

GnomAD4 genome AF: 0.00589 AC: 897 AN: 152336 Hom.: 8 Cov.: 33 AF XY: 0.00642 AC XY: 478 AN XY: 74486

African (AFR) AF: 0.000889 AC: 37 AN: 41598

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0260 AC: 276 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00736 AC: 501 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00461 Hom.: 1

Bravo AF: 0.00458

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00677 AC: 55

ExAC AF: 0.00681 AC: 819

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00788

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.076
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.039	B
Vest4		0.13
MVP		0.27
MPC		0.17
ClinPred		0.015	T
GERP RS		-2.1
Varity_R		0.055
gMVP		0.18
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs45560241; hg19: chr14-91739076; COSMIC: COSV57798306; COSMIC: COSV57798306;