chr7-77236998-A-G

Position:

• chr7-77236998-A-G

Variant summary

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

The NM_020879.3(CCDC146):​c.208A>G​(p.Lys70Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC146 NM_020879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

Genes affected

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

LOC105375359 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC146	NM_020879.3	c.208A>G	p.Lys70Glu	missense_variant	3/19	ENST00000285871.5	NP_065930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC146	ENST00000285871.5	c.208A>G	p.Lys70Glu	missense_variant	3/19	1	NM_020879.3	ENSP00000285871.4
CCDC146	ENST00000415750.5	c.208A>G	p.Lys70Glu	missense_variant	3/5	4		ENSP00000388649.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.208A>G (p.K70E) alteration is located in exon 3 (coding exon 2) of the CCDC146 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the lysine (K) at amino acid position 70 to be replaced by a glutamic acid (E). 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
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.046	.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.32		Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);
MVP		0.30
MPC		0.56
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.33
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1792748259; hg19: chr7-76866315;