16-1434490-C-T

Variant names:

• chr16-1434490-C-T
• rs565271689
• NM_001143980.3:c.1922G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001143980.3(CCDC154):​c.1922G>A​(p.Arg641Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,549,876 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CCDC154 NM_001143980.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.557

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017275453).
• BP6: Variant 16-1434490-C-T is Benign according to our data. Variant chr16-1434490-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3138557.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC154	NM_001143980.3	c.1922G>A	p.Arg641Gln	missense_variant	Exon 17 of 17	ENST00000389176.4	NP_001137452.1
PERCC1	NM_001365310.2	c.*1093C>T		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.1922G>A	p.Arg641Gln	missense_variant	Exon 17 of 17	5	NM_001143980.3	ENSP00000373828.4
PERCC1	ENST00000640283.2	c.*1093C>T		downstream_gene_variant		5	NM_001365310.2	ENSP00000492108.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000579 AC: 9 AN: 155426 Hom.: 0 AF XY: 0.0000606 AC XY: 5 AN XY: 82512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000918

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000444 AC: 62 AN: 1397590 Hom.: 0 Cov.: 50 AF XY: 0.0000566 AC XY: 39 AN XY: 689284

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.0000690

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152286 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000748 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 01, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.54
DEOGEN2	Benign	0.0019	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.016
Sift	Benign	0.16	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.022	B;.
Vest4		0.080
MutPred		0.29		Loss of catalytic residue at R648 (P = 0.0121);.;
MVP		0.014
MPC		0.00025
ClinPred		0.0070	T
GERP RS		-3.0
Varity_R		0.029
gMVP		0.029

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs565271689; hg19: chr16-1484491;