18-33215578-T-G

Position:

• chr18-33215578-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001105528.4(CCDC178):​c.2050A>C​(p.Ser684Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,317,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CCDC178 NM_001105528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.98

Genes affected

CCDC178 (HGNC:29588): (coiled-coil domain containing 178) Located in ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056785733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC178	NM_001105528.4	c.2050A>C	p.Ser684Arg	missense_variant	19/23	ENST00000383096.8	NP_001098998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC178	ENST00000383096.8	c.2050A>C	p.Ser684Arg	missense_variant	19/23	5	NM_001105528.4	ENSP00000372576.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000213 AC: 28 AN: 1317146 Hom.: 0 Cov.: 26 AF XY: 0.0000183 AC XY: 12 AN XY: 655000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000288

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000242

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.2050A>C (p.S684R) alteration is located in exon 18 (coding exon 17) of the CCDC178 gene. This alteration results from a A to C substitution at nucleotide position 2050, causing the serine (S) at amino acid position 684 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.017
DANN	Benign	0.15
DEOGEN2	Benign	0.0042	T;.;T;.;.;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.38	T;T;.;T;T;.;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;N;.;.;.;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.79	N;.;N;N;N;.;.
REVEL	Benign	0.026
Sift	Benign	0.23	T;.;T;T;T;.;.
Sift4G	Benign	0.56	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;B;B;B;.
Vest4		0.17
MutPred		0.16		Loss of phosphorylation at S684 (P = 0.0256);.;Loss of phosphorylation at S684 (P = 0.0256);.;Loss of phosphorylation at S684 (P = 0.0256);Loss of phosphorylation at S684 (P = 0.0256);Loss of phosphorylation at S684 (P = 0.0256);
MVP		0.048
MPC		0.018
ClinPred		0.097	T
GERP RS		-8.3
Varity_R		0.082
gMVP		0.030

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: rs774108139; hg19: chr18-30795542;