1-93264813-A-C

Variant names:

• chr1-93264813-A-C
• rs754019429
• NM_001378204.1:c.3797A>C

Variant summary

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

The NM_001378204.1(CCDC18):​c.3797A>C​(p.Glu1266Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000166 in 1,613,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CCDC18 NM_001378204.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

Genes affected

CCDC18 (HGNC:30370): (coiled-coil domain containing 18)

CCDC18-AS1 (HGNC:52262): (CCDC18 antisense RNA 1)

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=0.16732332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC18	NM_001378204.1	c.3797A>C	p.Glu1266Ala	missense_variant	Exon 27 of 29	ENST00000690025.1	NP_001365133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC18	ENST00000690025.1	c.3797A>C	p.Glu1266Ala	missense_variant	Exon 27 of 29		NM_001378204.1	ENSP00000510597.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 35 AN: 249194 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135200

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461228 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 121 AN XY: 726954

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74374

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3797A>C (p.E1266A) alteration is located in exon 27 (coding exon 26) of the CCDC18 gene. This alteration results from a A to C substitution at nucleotide position 3797, causing the glutamic acid (E) at amino acid position 1266 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;N
REVEL	Benign	0.11
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.073	T;T
Vest4		0.33
MVP		0.62
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.25

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: rs754019429; hg19: chr1-93730370;