NM_001080414.4:c.5654G>A

Variant names:

• chr14-91273058-C-T
• rs61742126
• NM_001080414.4:c.5654G>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.5654G>A​(p.Arg1885His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,556,670 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. R1885C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.34
• Publications: 0 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• spinocerebellar ataxia type 40

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.007236898).
• BP6: Variant 14-91273058-C-T is Benign according to our data. Variant chr14-91273058-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158115.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 = 0.00244 (372/152306) while in subpopulation AFR AF = 0.00842 (350/41568). AF 95% confidence interval is 0.00769. There are 2 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	NM_001080414.4	MANE Select	c.5654G>A	p.Arg1885His	missense	Exon 30 of 30	NP_001073883.2
	CCDC88C	NR_189158.1		n.5931G>A		non_coding_transcript_exon	Exon 31 of 31
	CCDC88C	NR_189159.1		n.6226G>A		non_coding_transcript_exon	Exon 31 of 31

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.5654G>A	p.Arg1885His	missense	Exon 30 of 30	ENSP00000374507.6
	CCDC88C	ENST00000556726.5	TSL:5	c.*1488G>A		3_prime_UTR	Exon 7 of 7	ENSP00000452406.1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000582 AC: 93 AN: 159856 AF XY: 0.000354

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000644

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000813

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000273 AC: 384 AN: 1404364 Hom.: 1 Cov.: 34 AF XY: 0.000245 AC XY: 170 AN XY: 693242

African (AFR) AF: 0.00819 AC: 264 AN: 32220

American (AMR) AF: 0.000744 AC: 28 AN: 37612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36822

South Asian (SAS) AF: 0.0000622 AC: 5 AN: 80442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44112

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5658

European-Non Finnish (NFE) AF: 0.0000406 AC: 44 AN: 1083998

Other (OTH) AF: 0.000721 AC: 42 AN: 58256

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74470

African (AFR) AF: 0.00842 AC: 350 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.00305

ESP6500AA AF: 0.00570 AC: 20

ESP6500EA AF: 0.000644 AC: 5

ExAC AF: 0.000523 AC: 61

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CCDC88C-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.39
MVP		0.81
MPC		0.67
ClinPred		0.036	T
GERP RS		5.1
Varity_R		0.23
gMVP		0.22
Mutation Taster		=96/4	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: rs61742126; hg19: chr14-91739402;