rs151102993

Positions:

• chr14-91283338-G-A

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.4621C>T​(p.Arg1541Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,296 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: CCDC88C NM_001080414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.76

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=0.0054469407).
• BP6: Variant 14-91283338-G-A is Benign according to our data. Variant chr14-91283338-G-A is described in ClinVar as [Benign]. Clinvar id is 158113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000446 (68/152334) while in subpopulation EAS AF= 0.0106 (55/5190). AF 95% confidence interval is 0.00836. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4	c.4621C>T	p.Arg1541Cys	missense_variant	26/30	ENST00000389857.11
CCDC88C	XM_011536796.3	c.4513C>T	p.Arg1505Cys	missense_variant	26/30
CCDC88C	XM_047431418.1	c.4354C>T	p.Arg1452Cys	missense_variant	23/27
CCDC88C	XM_047431419.1	c.4621C>T	p.Arg1541Cys	missense_variant	26/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11	c.4621C>T	p.Arg1541Cys	missense_variant	26/30	5	NM_001080414.4	P1
CCDC88C	ENST00000334448.5	n.286C>T		non_coding_transcript_exon_variant	1/6	1
CCDC88C	ENST00000556726.5	c.*455C>T		3_prime_UTR_variant	3/7	5

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00124 AC: 305 AN: 246376 Hom.: 3 AF XY: 0.00122 AC XY: 163 AN XY: 134000

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000318 AC: 464 AN: 1460962 Hom.: 3 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 726678

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00975

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74488

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000559 Hom.: 1

Bravo AF: 0.000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00120 AC: 145

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 15, 2016

- -

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	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.0018
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.065
Sift	Benign	0.076	T;D
Sift4G	Benign	0.18	T;T
Polyphen		0.088	.;B
Vest4		0.33
MVP		0.63
MPC		0.19
ClinPred		0.054	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151102993; hg19: chr14-91749682;