chr16-1434740-C-G

Variant names:

• chr16-1434740-C-G
• rs1314775175
• NM_001143980.3:c.1805G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143980.3(CCDC154):​c.1805G>C​(p.Arg602Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R602W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CCDC154 NM_001143980.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12557754).

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.1805G>C	p.Arg602Pro	missense	Exon 16 of 17	NP_001137452.1	A6NI56

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC154	ENST00000389176.4	TSL:5 MANE Select	c.1805G>C	p.Arg602Pro	missense	Exon 16 of 17	ENSP00000373828.4	A6NI56
	CCDC154	ENST00000409671.5	TSL:1	c.1370G>C	p.Arg457Pro	missense	Exon 15 of 16	ENSP00000386744.1	B7ZBA8
	CCDC154	ENST00000463299.2	TSL:1	n.322+11G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393730 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 687646

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078792

Other (OTH) AF: 0.00 AC: 0 AN: 57924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.5
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-2.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Uncertain	0.016	D
Polyphen		0.87	P
Vest4		0.33
MutPred		0.45		Loss of MoRF binding (P = 0.0038)
MVP		0.014
MPC		0.00025
ClinPred		0.26	T
GERP RS		-2.8
Varity_R		0.16
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1314775175; hg19: chr16-1484741;