chr5-69282889-C-A

Position:

• chr5-69282889-C-A

Variant summary

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

The NM_176816.5(CCDC125):​c.1376G>T​(p.Arg459Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCDC125 NM_176816.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06400645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC125	NM_176816.5	c.1376G>T	p.Arg459Leu	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.1376G>T	p.Arg459Leu	missense_variant	12/12	5	NM_176816.5	ENSP00000379754	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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 02, 2023

The c.1376G>T (p.R459L) alteration is located in exon 11 (coding exon 11) of the CCDC125 gene. This alteration results from a G to T substitution at nucleotide position 1376, causing the arginine (R) at amino acid position 459 to be replaced by a leucine (L). 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	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.23
DANN	Benign	0.95
DEOGEN2	Benign	0.0046	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.017	B;B;.
Vest4		0.11
MutPred		0.23		Loss of methylation at K460 (P = 0.0388);Loss of methylation at K460 (P = 0.0388);.;
MVP		0.085
MPC		0.083
ClinPred		0.055	T
GERP RS		-1.7
Varity_R		0.042
gMVP		0.047

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-68578716;