16-30006206-C-T

Variant summary

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

The NM_003586.3(DOC2A):​c.1183G>A​(p.Gly395Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,585,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

DOC2A
NM_003586.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29
Variant links:
Genes affected
DOC2A (HGNC:2985): (double C2 domain alpha) There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2-like domains. DOC2A and DOC2B are encoded by different genes; these genes are at times confused with the unrelated DAB2 gene which was initially named DOC-2. DOC2A is mainly expressed in brain and is suggested to be involved in Ca(2+)-dependent neurotransmitter release. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

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=0.088641554).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOC2ANM_003586.3 linkc.1183G>A p.Gly395Arg missense_variant Exon 11 of 11 ENST00000350119.9 NP_003577.2 Q14183-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOC2AENST00000350119.9 linkc.1183G>A p.Gly395Arg missense_variant Exon 11 of 11 1 NM_003586.3 ENSP00000340017.4 Q14183-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152110
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000350
AC:
7
AN:
199764
Hom.:
0
AF XY:
0.0000276
AC XY:
3
AN XY:
108678
show subpopulations
Gnomad AFR exome
AF:
0.0000843
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:
0.0000692
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000719
AC:
103
AN:
1433296
Hom.:
0
Cov.:
31
AF XY:
0.0000760
AC XY:
54
AN XY:
710816
show subpopulations
Gnomad4 AFR exome
AF:
0.0000605
Gnomad4 AMR exome
AF:
0.0000504
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:
0.0000891
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152110
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000848
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000415
AC:
5

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 30, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1183G>A (p.G395R) alteration is located in exon 11 (coding exon 10) of the DOC2A gene. This alteration results from a G to A substitution at nucleotide position 1183, causing the glycine (G) at amino acid position 395 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
0.17
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.054
T;T;T;T
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.79
.;T;.;.
M_CAP
Uncertain
0.086
D
MetaRNN
Benign
0.089
T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.5
L;L;L;L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.56
N;.;N;N
REVEL
Benign
0.086
Sift
Uncertain
0.0060
D;.;D;D
Sift4G
Uncertain
0.0090
D;D;D;D
Polyphen
0.026
B;B;B;B
Vest4
0.51
MutPred
0.24
Gain of methylation at G395 (P = 0.0212);Gain of methylation at G395 (P = 0.0212);Gain of methylation at G395 (P = 0.0212);Gain of methylation at G395 (P = 0.0212);
MVP
0.64
MPC
0.76
ClinPred
0.11
T
GERP RS
3.2
Varity_R
0.077
gMVP
0.42

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: rs756118173; hg19: chr16-30017527; COSMIC: COSV58752441; COSMIC: COSV58752441; API