chr5-69320404-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_176816.5(CCDC125):​c.137A>T​(p.His46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,070 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: 𝑓 0.000059 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

CCDC125
NM_176816.5 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0570
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.03306961).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC125NM_176816.5 linkuse as main transcriptc.137A>T p.His46Leu missense_variant 2/12 ENST00000396496.7 NP_789786.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC125ENST00000396496.7 linkuse as main transcriptc.137A>T p.His46Leu missense_variant 2/125 NM_176816.5 ENSP00000379754 P1Q86Z20-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152204
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251476
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000759
AC:
111
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.0000880
AC XY:
64
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000908
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152204
Hom.:
0
Cov.:
31
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 24, 2022The c.137A>T (p.H46L) alteration is located in exon 1 (coding exon 1) of the CCDC125 gene. This alteration results from a A to T substitution at nucleotide position 137, causing the histidine (H) at amino acid position 46 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
0.083
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
3.0
DANN
Benign
0.45
DEOGEN2
Benign
0.0077
T;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.035
N
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.033
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L;L;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.69
N;N;N
REVEL
Benign
0.037
Sift
Benign
0.67
T;T;T
Sift4G
Benign
0.65
T;T;T
Polyphen
0.11
B;B;B
Vest4
0.19
MVP
0.030
MPC
0.098
ClinPred
0.031
T
GERP RS
-3.2
Varity_R
0.048
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368303091; hg19: chr5-68616231; API