14-91313938-C-G

Variant names:

• chr14-91313938-C-G
• rs78468999
• NM_001080414.4:c.1878G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080414.4(CCDC88C):​c.1878G>C​(p.Lys626Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,400 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K626K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.674
• 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: 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01115182).
• BP6: Variant 14-91313938-C-G is Benign according to our data. Variant chr14-91313938-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447014.
• BS2: High Homozygotes in GnomAdExome4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	NM_001080414.4	MANE Select	c.1878G>C	p.Lys626Asn	missense	Exon 15 of 30	NP_001073883.2
	CCDC88C	NR_189158.1		n.2008G>C		non_coding_transcript_exon	Exon 15 of 31
	CCDC88C	NR_189159.1		n.2008G>C		non_coding_transcript_exon	Exon 15 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.1878G>C	p.Lys626Asn	missense	Exon 15 of 30	ENSP00000374507.6
	CCDC88C	ENST00000557507.1	TSL:2	n.*5G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00113 AC: 281 AN: 248870 AF XY: 0.00115

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00376

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00108 AC: 1577 AN: 1461314 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 769 AN XY: 726980

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000800 AC: 69 AN: 86258

European-Finnish (FIN) AF: 0.00421 AC: 223 AN: 53012

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1161 AN: 1111870

Other (OTH) AF: 0.00106 AC: 64 AN: 60366

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74354

African (AFR) AF: 0.000193 AC: 8 AN: 41490

American (AMR) AF: 0.000458 AC: 7 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5144

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.00472 AC: 50 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67996

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.67
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.49
MutPred		0.40		Loss of ubiquitination at K626 (P = 0.0074)
MVP		0.62
MPC		0.60
ClinPred		0.057	T
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.32
gMVP		0.25
Mutation Taster		=63/37	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: rs78468999; hg19: chr14-91780282;