16-1434476-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.1936G>A​(p.Val646Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,549,956 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 0.00024 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CCDC154
NM_001143980.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.185
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]
PERCC1 (HGNC:52293): (proline and glutamate rich with coiled coil 1) Predicted to be involved in digestive tract morphogenesis and enteroendocrine cell differentiation. Implicated in congenital diarrhea. [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=0.014546037).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC154NM_001143980.3 linkc.1936G>A p.Val646Ile missense_variant Exon 17 of 17 ENST00000389176.4 NP_001137452.1 A6NI56
PERCC1NM_001365310.2 linkc.*1079C>T downstream_gene_variant ENST00000640283.2 NP_001352239.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC154ENST00000389176.4 linkc.1936G>A p.Val646Ile missense_variant Exon 17 of 17 5 NM_001143980.3 ENSP00000373828.4 A6NI56A0A590PWR5
PERCC1ENST00000640283.2 linkc.*1079C>T downstream_gene_variant 5 NM_001365310.2 ENSP00000492108.2 A0A1W2PR82

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152156
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000893
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000578
AC:
9
AN:
155804
Hom.:
0
AF XY:
0.0000484
AC XY:
4
AN XY:
82688
show subpopulations
Gnomad AFR exome
AF:
0.00114
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000114
AC:
16
AN:
1397682
Hom.:
0
Cov.:
50
AF XY:
0.0000102
AC XY:
7
AN XY:
689338
show subpopulations
Gnomad4 AFR exome
AF:
0.000475
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152274
Hom.:
0
Cov.:
34
AF XY:
0.000255
AC XY:
19
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000890
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000223
ESP6500AA
AF:
0.000723
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000112
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1936G>A (p.V646I) alteration is located in exon 17 (coding exon 17) of the CCDC154 gene. This alteration results from a G to A substitution at nucleotide position 1936, causing the valine (V) at amino acid position 646 to be replaced by an isoleucine (I). 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
-0.63
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
2.0
DANN
Benign
0.66
DEOGEN2
Benign
0.0029
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.025
N
LIST_S2
Benign
0.40
T;T
M_CAP
Benign
0.0029
T
MetaRNN
Benign
0.015
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.37
N;N
REVEL
Benign
0.0070
Sift
Benign
0.23
T;T
Sift4G
Benign
0.36
T;T
Polyphen
0.0070
B;.
Vest4
0.028
MVP
0.014
MPC
0.00025
ClinPred
0.0032
T
GERP RS
0.65
Varity_R
0.029
gMVP
0.019

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs369805573; hg19: chr16-1484477; API