18-33223142-C-A

Position:

• chr18-33223142-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105528.4(CCDC178):​c.1896G>T​(p.Lys632Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000034 (0 hom.)
• Consequence: CCDC178 NM_001105528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.330

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14722025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC178	NM_001105528.4	c.1896G>T	p.Lys632Asn	missense_variant	18/23	ENST00000383096.8	NP_001098998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC178	ENST00000383096.8	c.1896G>T	p.Lys632Asn	missense_variant	18/23	5	NM_001105528.4	ENSP00000372576.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454148 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Aug 29, 2024

The c.1896G>T (p.K632N) alteration is located in exon 17 (coding exon 16) of the CCDC178 gene. This alteration results from a G to T substitution at nucleotide position 1896, causing the lysine (K) at amino acid position 632 to be replaced by an asparagine (N). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Benign	0.0099	T;.;T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.74	T;T;.;T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;.;N;N;.;.
REVEL	Benign	0.032
Sift	Pathogenic	0.0	D;.;D;D;.;.
Sift4G	Uncertain	0.059	T;D;T;T;T;T
Polyphen		0.99	D;.;D;D;D;.
Vest4		0.11
MutPred		0.21		Loss of methylation at K632 (P = 0.0384);.;Loss of methylation at K632 (P = 0.0384);Loss of methylation at K632 (P = 0.0384);Loss of methylation at K632 (P = 0.0384);Loss of methylation at K632 (P = 0.0384);
MVP		0.081
MPC		0.13
ClinPred		0.64	D
GERP RS		-0.29
Varity_R		0.16
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2059258139; hg19: chr18-30803106;