chr3-46925534-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001277074.2(CCDC12):ā€‹c.166G>Cā€‹(p.Glu56Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000426 in 1,572,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 33)
Exomes š‘“: 0.000041 ( 0 hom. )

Consequence

CCDC12
NM_001277074.2 missense, splice_region

Scores

1
6
12
Splicing: ADA: 0.9552
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.10
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31805453).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC12NM_001277074.2 linkuse as main transcriptc.166G>C p.Glu56Gln missense_variant, splice_region_variant 3/7 ENST00000683445.1 NP_001264003.1
CCDC12NM_144716.6 linkuse as main transcriptc.205G>C p.Glu69Gln missense_variant, splice_region_variant 4/8 NP_653317.2
CCDC12NR_102269.2 linkuse as main transcriptn.219G>C splice_region_variant, non_coding_transcript_exon_variant 3/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC12ENST00000683445.1 linkuse as main transcriptc.166G>C p.Glu56Gln missense_variant, splice_region_variant 3/7 NM_001277074.2 ENSP00000508011 P1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152170
Hom.:
0
Cov.:
33
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:
0.0000135
AC:
3
AN:
222792
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
119316
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:
0.0000294
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000408
AC:
58
AN:
1420674
Hom.:
0
Cov.:
30
AF XY:
0.0000385
AC XY:
27
AN XY:
700454
show subpopulations
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:
0.0000124
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000479
Gnomad4 OTH exome
AF:
0.0000854
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74328
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:
0.0000434
Hom.:
0
Bravo
AF:
0.0000642
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

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 GeneticsOct 26, 2022The c.205G>C (p.E69Q) alteration is located in exon 3 (coding exon 3) of the CCDC12 gene. This alteration results from a G to C substitution at nucleotide position 205, causing the glutamic acid (E) at amino acid position 69 to be replaced by a glutamine (Q). 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
0.18
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.015
T;.;T;T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.32
T;T;T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.1
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.78
.;N;.;.
REVEL
Benign
0.24
Sift
Benign
0.29
.;T;.;.
Sift4G
Benign
0.48
T;T;T;.
Polyphen
0.84
P;.;.;.
Vest4
0.40
MVP
0.41
MPC
0.67
ClinPred
0.72
D
GERP RS
5.5
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.15
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.96
dbscSNV1_RF
Pathogenic
0.85
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: rs376223547; hg19: chr3-46967024; API