rs139544500

Variant names:

• chr14-91281488-C-T
• rs139544500
• NM_001080414.4:c.4668G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080414.4(CCDC88C):​c.4668G>A​(p.Leu1556Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,613,946 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (53 hom.)
• Consequence: CCDC88C NM_001080414.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.134
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-91281488-C-T is Benign according to our data. Variant chr14-91281488-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00489 (745/152306) while in subpopulation AMR AF = 0.00725 (111/15300). AF 95% confidence interval is 0.00656. There are 3 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.4668G>A	p.Leu1556Leu	synonymous	Exon 27 of 30	NP_001073883.2	Q9P219-1
	CCDC88C	NR_189158.1		n.4798G>A		non_coding_transcript_exon	Exon 27 of 31
	CCDC88C	NR_189159.1		n.5240G>A		non_coding_transcript_exon	Exon 28 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC88C	ENST00000389857.11	TSL:5 MANE Select	c.4668G>A	p.Leu1556Leu	synonymous	Exon 27 of 30	ENSP00000374507.6	Q9P219-1
	CCDC88C	ENST00000334448.5	TSL:1	n.333G>A		non_coding_transcript_exon	Exon 2 of 6
	CCDC88C	ENST00000556726.5	TSL:5	c.*502G>A		3_prime_UTR	Exon 4 of 7	ENSP00000452406.1	H0YJX5

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 747 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00563 AC: 1403 AN: 249274 AF XY: 0.00551

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00701

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00875

GnomAD4 exome AF: 0.00767 AC: 11205 AN: 1461640 Hom.: 53 Cov.: 31 AF XY: 0.00738 AC XY: 5368 AN XY: 727108

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 343 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86258

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53390

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00884 AC: 9824 AN: 1111824

Other (OTH) AF: 0.00787 AC: 475 AN: 60372

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74474

African (AFR) AF: 0.00149 AC: 62 AN: 41552

American (AMR) AF: 0.00725 AC: 111 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00709 AC: 482 AN: 68020

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00682 Hom.: 2

Bravo AF: 0.00578

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.0101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hydrocephalus, nonsyndromic, autosomal recessive 1;C4518336:Spinocerebellar ataxia type 40 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.1
DANN	Benign	0.62
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139544500; hg19: chr14-91747832; COSMIC: COSV57796003; COSMIC: COSV57796003;