chr3-46923616-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001277074.2(CCDC12):ā€‹c.297C>Gā€‹(p.Ile99Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CCDC12
NM_001277074.2 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.479
Variant links:
Genes affected
CCDC12 (HGNC:28332): (coiled-coil domain containing 12) Predicted to be part of U2-type spliceosomal complex and post-mRNA release spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC12NM_001277074.2 linkuse as main transcriptc.297C>G p.Ile99Met missense_variant 4/7 ENST00000683445.1 NP_001264003.1
CCDC12NM_144716.6 linkuse as main transcriptc.336C>G p.Ile112Met missense_variant 5/8 NP_653317.2
CCDC12NR_102269.2 linkuse as main transcriptn.350C>G non_coding_transcript_exon_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC12ENST00000683445.1 linkuse as main transcriptc.297C>G p.Ile99Met missense_variant 4/7 NM_001277074.2 ENSP00000508011 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.91e-7
AC:
1
AN:
1447162
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
718820
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000231
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 GeneticsMar 17, 2023The c.336C>G (p.I112M) alteration is located in exon 4 (coding exon 4) of the CCDC12 gene. This alteration results from a C to G substitution at nucleotide position 336, causing the isoleucine (I) at amino acid position 112 to be replaced by a methionine (M). 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
0.21
BayesDel_addAF
Benign
0.0027
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
4.3
DANN
Benign
0.91
DEOGEN2
Benign
0.059
T;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.87
FATHMM_MKL
Benign
0.42
N
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.036
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.9
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.7
.;N
REVEL
Uncertain
0.53
Sift
Benign
0.038
.;D
Sift4G
Uncertain
0.045
D;D
Polyphen
0.88
P;.
Vest4
0.57
MutPred
0.58
Gain of relative solvent accessibility (P = 0.0483);.;
MVP
0.51
MPC
0.43
ClinPred
0.97
D
GERP RS
-6.9
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.13
gMVP
0.12

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

LitVar

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

Other links and lift over

dbSNP: rs141076138; hg19: chr3-46965106; API