5-69282866-A-C

Position:

• chr5-69282866-A-C

Variant summary

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

The NM_176816.5(CCDC125):​c.1399T>G​(p.Leu467Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC125 NM_176816.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.282

Genes affected

CCDC125 (HGNC:28924): (coiled-coil domain containing 125) Enables identical protein binding activity. Involved in activation of GTPase activity; negative regulation of Rho protein signal transduction; and negative regulation of cell motility. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CCDC125 (HGNC:):

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=0.07927883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC125	NM_176816.5	c.1399T>G	p.Leu467Val	missense_variant	12/12	ENST00000396496.7	NP_789786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC125	ENST00000396496.7	c.1399T>G	p.Leu467Val	missense_variant	12/12	5	NM_176816.5	ENSP00000379754.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 11, 2024

The c.1399T>G (p.L467V) alteration is located in exon 11 (coding exon 11) of the CCDC125 gene. This alteration results from a T to G substitution at nucleotide position 1399, causing the leucine (L) at amino acid position 467 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.27
DANN	Benign	0.91
DEOGEN2	Benign	0.0033	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.055	N
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.018	B;B;.
Vest4		0.044
MutPred		0.41		Loss of catalytic residue at L467 (P = 0.103);Loss of catalytic residue at L467 (P = 0.103);.;
MVP		0.16
MPC		0.067
ClinPred		0.073	T
GERP RS		-3.5
Varity_R		0.035
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1752636360; hg19: chr5-68578693;