chr3-46976732-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001277074.2(CCDC12):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CCDC12
NM_001277074.2 start_lost

Scores

4
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30
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 Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CCDC12NM_001277074.2 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/7 ENST00000683445.1 NP_001264003.1
CCDC12NM_144716.6 linkuse as main transcriptc.40A>T p.Met14Leu missense_variant 2/8 NP_653317.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CCDC12ENST00000683445.1 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/7 NM_001277074.2 ENSP00000508011 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000426
AC:
1
AN:
234590
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
126986
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000301
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1453490
Hom.:
0
Cov.:
34
AF XY:
0.00000277
AC XY:
2
AN XY:
722268
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000914
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.:
31
Bravo
AF:
0.0000113

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 GeneticsSep 29, 2022The c.40A>T (p.M14L) alteration is located in exon 1 (coding exon 1) of the CCDC12 gene. This alteration results from a A to T substitution at nucleotide position 40, causing the methionine (M) at amino acid position 14 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
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
24
DANN
Benign
0.92
DEOGEN2
Benign
0.012
T;.;T;T
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Benign
0.65
D
LIST_S2
Uncertain
0.90
D;T;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Benign
-0.33
T
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
0.010
N;N;N;.
REVEL
Uncertain
0.32
Sift
Benign
0.62
T;D;T;.
Sift4G
Pathogenic
0.0
D;T;D;.
Polyphen
0.52
P;.;.;.
Vest4
0.90
MutPred
0.94
Gain of glycosylation at T5 (P = 0.0313);.;Gain of glycosylation at T5 (P = 0.0313);Gain of glycosylation at T5 (P = 0.0313);
MVP
0.67
MPC
0.22
ClinPred
0.91
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.48
gMVP
0.22

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: rs1425572022; hg19: chr3-47018222; API