2-131528005-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001258306.3(CCDC74A):​c.35C>G​(p.Pro12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000023 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CCDC74A
NM_001258306.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0630
Variant links:
Genes affected
CCDC74A (HGNC:25197): (coiled-coil domain containing 74A)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21103531).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC74ANM_001258306.3 linkc.35C>G p.Pro12Arg missense_variant Exon 1 of 8 ENST00000409856.8 NP_001245235.1 Q96AQ1-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC74AENST00000409856.8 linkc.35C>G p.Pro12Arg missense_variant Exon 1 of 8 1 NM_001258306.3 ENSP00000387009.3 Q96AQ1-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151380
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000484
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000228
AC:
3
AN:
1314336
Hom.:
0
Cov.:
30
AF XY:
0.00000156
AC XY:
1
AN XY:
640652
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000192
Gnomad4 OTH exome
AF:
0.0000185
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151380
Hom.:
0
Cov.:
31
AF XY:
0.0000271
AC XY:
2
AN XY:
73918
show subpopulations
Gnomad4 AFR
AF:
0.0000484
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.35C>G (p.P12R) alteration is located in exon 1 (coding exon 1) of the CCDC74A gene. This alteration results from a C to G substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 to be replaced by an arginine (R). 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
0.24
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;T;.
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.069
N
LIST_S2
Benign
0.65
T;T;T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
0.55
N;.;N
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.8
D;.;D
REVEL
Benign
0.067
Sift
Pathogenic
0.0
D;.;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.18
MutPred
0.24
Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);
MVP
0.30
MPC
1.9
ClinPred
0.88
D
GERP RS
2.0
Varity_R
0.12
gMVP
0.23

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: rs767296333; hg19: chr2-132285578; API