14-91278091-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080414.4(CCDC88C):c.4889G>A(p.Arg1630His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,612,316 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R1630L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.721

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053323507).
• BP6: Variant 14-91278091-C-T is Benign according to our data. Variant chr14-91278091-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 447022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91278091-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00401 (610/152308) while in subpopulation AFR AF= 0.014 (582/41572). AF 95% confidence interval is 0.0131. There are 3 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.4889G>A	p.Arg1630His	missense_variant	29/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.4781G>A	p.Arg1594His	missense_variant	29/30
CCDC88C	XM_047431418.1	c.4622G>A	p.Arg1541His	missense_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.4889G>A	p.Arg1630His	missense_variant	29/30	5	NM_001080414.4	P1
CCDC88C	ENST00000334448.5	n.701G>A		non_coding_transcript_exon_variant	5/6	1
CCDC88C	ENST00000556726.5	c.*723G>A		3_prime_UTR_variant	6/7	5
CCDC88C	ENST00000557455.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 611 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000872 AC: 212 AN: 242998 Hom.: 0 AF XY: 0.000664 AC XY: 88 AN XY: 132620

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0000880

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000395 AC: 576 AN: 1460008 Hom.: 6 Cov.: 32 AF XY: 0.000330 AC XY: 240 AN XY: 726214

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74482

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000797 Hom.: 3

Bravo AF: 0.00454

ESP6500AA AF: 0.0104 AC: 42

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00122 AC: 148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 30, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	0.037
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.83	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;T
Sift4G	Benign	0.074	T;T
Polyphen		0.98	.;D
Vest4		0.23
MVP		0.59
MPC		0.17
ClinPred		0.022	T
GERP RS		3.4
Varity_R		0.033
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs115510695; hg19: chr14-91744435;