5-69313986-T-A

Variant summary

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

The NM_176816.5(CCDC125):c.365A>T(p.Glu122Val) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC125 NM_176816.5 missense, splice_region
• Scores: Splicing: ADA: 0.1770
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 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=0.12531316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC125	NM_176816.5	c.365A>T	p.Glu122Val	missense_variant, splice_region_variant	3/12	ENST00000396496.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC125	ENST00000396496.7	c.365A>T	p.Glu122Val	missense_variant, splice_region_variant	3/12	5	NM_176816.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Aug 02, 2021

The c.365A>T (p.E122V) alteration is located in exon 2 (coding exon 2) of the CCDC125 gene. This alteration results from a A to T substitution at nucleotide position 365, causing the glutamic acid (E) at amino acid position 122 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	0.26
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	0.74	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.097
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.53	P;P;.
Vest4		0.45
MutPred		0.25		Gain of catalytic residue at E122 (P = 0.0042);Gain of catalytic residue at E122 (P = 0.0042);.;
MVP		0.061
MPC		0.080
ClinPred		0.78	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.25
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: -1

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: chr5-68609813;