19-407446-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136263.2(C2CD4C):​c.916C>T​(p.Arg306Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,472,472 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

C2CD4C
NM_001136263.2 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21
Variant links:
Genes affected
C2CD4C (HGNC:29417): (C2 calcium dependent domain containing 4C) Predicted to be active in cytosol. [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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C2CD4CNM_001136263.2 linkc.916C>T p.Arg306Trp missense_variant Exon 2 of 2 ENST00000332235.8 NP_001129735.1 Q8TF44
C2CD4CXM_011527694.2 linkc.916C>T p.Arg306Trp missense_variant Exon 2 of 3 XP_011525996.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C2CD4CENST00000332235.8 linkc.916C>T p.Arg306Trp missense_variant Exon 2 of 2 2 NM_001136263.2 ENSP00000328677.4 Q8TF44

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151910
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.0000267
AC:
2
AN:
74842
Hom.:
0
AF XY:
0.0000252
AC XY:
1
AN XY:
39710
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000659
Gnomad ASJ exome
AF:
0.000324
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:
0.0000197
AC:
26
AN:
1320562
Hom.:
0
Cov.:
31
AF XY:
0.0000201
AC XY:
13
AN XY:
646326
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000153
Gnomad4 ASJ exome
AF:
0.0000976
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000148
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000124
Gnomad4 OTH exome
AF:
0.0000912
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151910
Hom.:
0
Cov.:
33
AF XY:
0.0000809
AC XY:
6
AN XY:
74198
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000957
Bravo
AF:
0.0000831

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.916C>T (p.R306W) alteration is located in exon 2 (coding exon 1) of the C2CD4C gene. This alteration results from a C to T substitution at nucleotide position 916, causing the arginine (R) at amino acid position 306 to be replaced by a tryptophan (W). 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
0.14
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.74
T
M_CAP
Pathogenic
0.92
D
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.2
L
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.38
Sift
Uncertain
0.021
D
Sift4G
Uncertain
0.0080
D
Polyphen
1.0
D
Vest4
0.26
MutPred
0.46
Loss of disorder (P = 0.0054);
MVP
0.32
ClinPred
0.65
D
GERP RS
0.88
Varity_R
0.088
gMVP
0.54

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: rs1035470242; hg19: chr19-407446; API