chr5-69292235-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.1052A>T​(p.His351Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,424 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: 0.0000027 ( 0 hom. )

Consequence

CCDC125
NM_176816.5 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.755
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]

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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=0.050041646).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC125NM_176816.5 linkuse as main transcriptc.1052A>T p.His351Leu missense_variant 10/12 ENST00000396496.7 NP_789786.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC125ENST00000396496.7 linkuse as main transcriptc.1052A>T p.His351Leu missense_variant 10/125 NM_176816.5 ENSP00000379754 P1Q86Z20-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461424
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727002
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000331
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000227

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 GeneticsNov 18, 2023The c.1052A>T (p.H351L) alteration is located in exon 9 (coding exon 9) of the CCDC125 gene. This alteration results from a A to T substitution at nucleotide position 1052, causing the histidine (H) at amino acid position 351 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
0.092
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
8.4
DANN
Benign
0.80
DEOGEN2
Benign
0.0013
T;T;.
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.52
D
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.050
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
N;N;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.55
N;N;N
REVEL
Benign
0.015
Sift
Benign
0.65
T;T;T
Sift4G
Benign
0.64
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.17
MutPred
0.29
Loss of methylation at K352 (P = 0.0854);Loss of methylation at K352 (P = 0.0854);.;
MVP
0.088
MPC
0.080
ClinPred
0.15
T
GERP RS
2.6
Varity_R
0.072
gMVP
0.062

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1754571155; hg19: chr5-68588062; API