Genetic Variant CCDC18:p.Met1229Thr (chr1-93264702-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378204.1(CCDC18):c.3686T>C(p.Met1229Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,599,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CCDC18
NM_001378204.1 missense, splice_region

Scores

Splicing: ADA: 0.7518

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378204.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC18	NM_001378204.1	MANE Select	c.3686T>C	p.Met1229Thr	missense splice_region	Exon 27 of 29	NP_001365133.1	A0A8I5KWA2
CCDC18	NM_001306076.1		c.3683T>C	p.Met1228Thr	missense splice_region	Exon 27 of 29	NP_001293005.1	Q6PH87
CCDC18	NM_206886.4		c.3686T>C	p.Met1229Thr	missense splice_region	Exon 27 of 28	NP_996769.3	Q6PH87

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC18	ENST00000690025.1	MANE Select	c.3686T>C	p.Met1229Thr	missense splice_region	Exon 27 of 29	ENSP00000510597.1	A0A8I5KWA2
CCDC18	ENST00000401026.7	TSL:1	c.3686T>C	p.Met1229Thr	missense splice_region	Exon 27 of 28	ENSP00000383808.3	E9PFB9
CCDC18	ENST00000447456.1	TSL:1	n.442T>C		splice_region non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246614

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1446972

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32992

American (AMR)

AF:

0.0000226

AC:

AN:

44196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.00

AC:

AN:

85042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1100322

Other (OTH)

AF:

0.00

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

M_CAP

Benign

0.0038

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

PhyloP100

3.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

REVEL

Benign

0.063

Sift

Benign

0.039

Sift4G

Benign

0.54

Vest4

0.59

MVP

0.28

ClinPred

0.38

GERP RS

5.8

Varity_R

0.20

gMVP

0.17

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.75

dbscSNV1_RF

Benign

0.46

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over