16-1436034-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001143980.3(CCDC154):​c.1540G>A​(p.Val514Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,550,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CCDC154
NM_001143980.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.370
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011388928).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC154NM_001143980.3 linkc.1540G>A p.Val514Met missense_variant Exon 14 of 17 ENST00000389176.4 NP_001137452.1 A6NI56

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC154ENST00000389176.4 linkc.1540G>A p.Val514Met missense_variant Exon 14 of 17 5 NM_001143980.3 ENSP00000373828.4 A6NI56A0A590PWR5
CCDC154ENST00000409671.5 linkc.1105G>A p.Val369Met missense_variant Exon 13 of 16 1 ENSP00000386744.1 B7ZBA8
CCDC154ENST00000483702.5 linkn.284+411G>A intron_variant Intron 3 of 5 3 ENSP00000456484.1 H3BS06

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
5
AN:
155960
Hom.:
0
AF XY:
0.0000242
AC XY:
2
AN XY:
82774
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000162
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000166
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000207
AC:
29
AN:
1398008
Hom.:
0
Cov.:
31
AF XY:
0.0000232
AC XY:
16
AN XY:
689524
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000505
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000176
Gnomad4 OTH exome
AF:
0.0000345
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000380
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1540G>A (p.V514M) alteration is located in exon 14 (coding exon 14) of the CCDC154 gene. This alteration results from a G to A substitution at nucleotide position 1540, causing the valine (V) at amino acid position 514 to be replaced by a methionine (M). 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
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
12
DANN
Benign
0.97
DEOGEN2
Benign
0.0073
T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.74
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.59
N;N
REVEL
Benign
0.056
Sift
Benign
0.080
T;T
Sift4G
Benign
0.17
T;T
Polyphen
0.94
P;.
Vest4
0.17
MVP
0.014
MPC
0.00025
ClinPred
0.10
T
GERP RS
-2.1
Varity_R
0.037
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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

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

Other links and lift over

dbSNP: rs556065475; hg19: chr16-1486035; API