16-1434452-C-G

Variant names:

• chr16-1434452-C-G
• rs750721196
• NM_001143980.3:c.1960G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143980.3(CCDC154):​c.1960G>C​(p.Glu654Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,398,034 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: not found (cov: 35)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CCDC154 NM_001143980.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.850

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084475845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC154	NM_001143980.3	c.1960G>C	p.Glu654Gln	missense_variant	Exon 17 of 17	ENST00000389176.4	NP_001137452.1
PERCC1	NM_001365310.2	c.*1055C>G		downstream_gene_variant		ENST00000640283.2	NP_001352239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC154	ENST00000389176.4	c.1960G>C	p.Glu654Gln	missense_variant	Exon 17 of 17	5	NM_001143980.3	ENSP00000373828.4
PERCC1	ENST00000640283.2	c.*1055C>G		downstream_gene_variant		5	NM_001365310.2	ENSP00000492108.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000128 AC: 2 AN: 156270 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82882

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000332

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1398034 Hom.: 0 Cov.: 60 AF XY: 0.0000102 AC XY: 7 AN XY: 689516

Gnomad4 AFR exome AF: 0.00

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: 0.0000139

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1960G>C (p.E654Q) alteration is located in exon 17 (coding exon 17) of the CCDC154 gene. This alteration results from a G to C substitution at nucleotide position 1960, causing the glutamic acid (E) at amino acid position 654 to be replaced by a glutamine (Q). 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	-0.31	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.0064	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.077
Sift	Benign	0.16	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.90	P;.
Vest4		0.19
MutPred		0.088		Loss of ubiquitination at K656 (P = 0.0384);.;
MVP		0.014
MPC		0.00025
ClinPred		0.085	T
GERP RS		1.6
Varity_R		0.051
gMVP		0.045

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs750721196; hg19: chr16-1484453;