Genetic Variant CCDC18:p.Lys1440delinsAsnLeu (chr1-93270780-A-ACCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PM4_SupportingBP6

The NM_001378204.1(CCDC18):c.4319_4320insCCT(p.Lys1440delinsAsnLeu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,545,196 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

CCDC18
NM_001378204.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.926

Variant links:

Genes affected

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

CCDC18 links:

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

CCDC18-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001378204.1. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 1-93270780-A-ACCT is Benign according to our data. Variant chr1-93270780-A-ACCT is described in ClinVar as [Likely_benign]. Clinvar id is 3047544.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC18	NM_001378204.1 link	c.4319_4320insCCT	p.Lys1440delinsAsnLeu	disruptive_inframe_insertion	Exon 28 of 29	ENST00000690025.1	NP_001365133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC18	ENST00000690025.1 link	c.4319_4320insCCT	p.Lys1440delinsAsnLeu	disruptive_inframe_insertion	Exon 28 of 29		NM_001378204.1	ENSP00000510597.1		A0A8I5KWA2

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

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:

0.000441

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000610

AC:

AN:

144208

Hom.:

AF XY:

0.000527

AC XY:

AN XY:

77838

show subpopulations

Gnomad AFR exome

AF:

0.000300

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000601

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00171

GnomAD4 exome

AF:

0.000399

AC:

556

AN:

1392848

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

265

AN XY:

687040

show subpopulations

Gnomad4 AFR exome

AF:

0.0000643

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000208

Gnomad4 NFE exome

AF:

0.000428

Gnomad4 OTH exome

AF:

0.000295

GnomAD4 genome

AF:

0.000715

AC:

109

AN:

152348

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000616

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CCDC18-related disorder

Benign:1

Nov 30, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over