14-91313907-G-C

Variant names:

• chr14-91313907-G-C
• rs7160308
• NM_001080414.4:c.1909C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080414.4(CCDC88C):​c.1909C>G​(p.Leu637Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,611,280 control chromosomes in the GnomAD database, including 171 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L637L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (75 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.29
• Publications: 3 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=0.001711458).
• BP6: Variant 14-91313907-G-C is Benign according to our data. Variant chr14-91313907-G-C is described in ClinVar as Benign. ClinVar VariationId is 158093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

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.1909C>G	p.Leu637Val	missense	Exon 15 of 30	NP_001073883.2
	CCDC88C	NR_189158.1		n.2039C>G		non_coding_transcript_exon	Exon 15 of 31
	CCDC88C	NR_189159.1		n.2039C>G		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.1909C>G	p.Leu637Val	missense	Exon 15 of 30	ENSP00000374507.6
	CCDC88C	ENST00000557507.1	TSL:2	n.*36C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2761 AN: 151438 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.00434 AC: 1075 AN: 247820 AF XY: 0.00335

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000668

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00177 AC: 2586 AN: 1459724 Hom.: 75 Cov.: 32 AF XY: 0.00153 AC XY: 1114 AN XY: 726198

African (AFR) AF: 0.0623 AC: 2085 AN: 33480

American (AMR) AF: 0.00333 AC: 149 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51604

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111746

Other (OTH) AF: 0.00457 AC: 276 AN: 60348

GnomAD4 genome AF: 0.0182 AC: 2759 AN: 151556 Hom.: 96 Cov.: 32 AF XY: 0.0176 AC XY: 1305 AN XY: 74028

African (AFR) AF: 0.0631 AC: 2605 AN: 41256

American (AMR) AF: 0.00637 AC: 97 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5118

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67892

Other (OTH) AF: 0.0176 AC: 37 AN: 2102

Alfa AF: 0.000867 Hom.: 3

Bravo AF: 0.0209

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0622 AC: 259

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00530 AC: 641

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.058
Sift	Benign	0.23	T
Sift4G	Benign	0.50	T
Polyphen		0.044	B
Vest4		0.19
MVP		0.49
MPC		0.15
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.10
gMVP		0.15
Mutation Taster		=97/3	polymorphism (auto)

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: rs7160308; hg19: chr14-91780251; COSMIC: COSV99062330; COSMIC: COSV99062330;