Genetic Variant CCDC154:p.Val514Leu (chr16-1436034-C-A) – 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_001143980.3(CCDC154):c.1540G>T(p.Val514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,550,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V514M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

CCDC154
NM_001143980.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.370

Publications

0 publications found

Variant links:

Genes affected

CCDC154 (HGNC:34454): (coiled-coil domain containing 154) Predicted to be involved in bone mineralization involved in bone maturation. Predicted to act upstream of or within bone resorption; odontogenesis of dentin-containing tooth; and tooth eruption. Predicted to be located in early endosome. [provided by Alliance of Genome Resources, Apr 2022]

CCDC154 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_001143980.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC154	NM_001143980.3	MANE Select	c.1540G>T	p.Val514Leu	missense	Exon 14 of 17	NP_001137452.1	A6NI56

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC154	ENST00000389176.4	TSL:5 MANE Select	c.1540G>T	p.Val514Leu	missense	Exon 14 of 17	ENSP00000373828.4	A6NI56
CCDC154	ENST00000409671.5	TSL:1	c.1105G>T	p.Val369Leu	missense	Exon 13 of 16	ENSP00000386744.1	B7ZBA8
CCDC154	ENST00000483702.5	TSL:3	n.284+411G>T		intron	N/A	ENSP00000456484.1	H3BS06

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000128

AC:

AN:

155960

AF XY:

0.00

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:

0.0000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000393

AC:

AN:

1398008

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

689524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000473

AC:

AN:

1078862

Other (OTH)

AF:

0.0000345

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000264

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

Benign

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0074

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.68

M_CAP

Benign

0.012

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

-0.37

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.24

REVEL

Benign

0.029

Sift

Benign

0.27

Sift4G

Benign

0.65

Polyphen

0.32

Vest4

0.23

MutPred

0.22

Gain of disorder (P = 0.0665)

MVP

0.014

MPC

0.00025

ClinPred

0.051

GERP RS

-2.1

Varity_R

0.046

gMVP

0.74

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.43

Position offset: -6

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over