Genetic Variant DOC2A:p.Glu364Lys (chr16-30006299-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_003586.3(DOC2A):c.1090G>A(p.Glu364Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000192 in 1,610,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

DOC2A
NM_003586.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

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]

DOC2A links:

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=0.32557184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOC2A	NM_003586.3 link	c.1090G>A	p.Glu364Lys	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
DOC2A	ENST00000350119.9 link	c.1090G>A	p.Glu364Lys	missense_variant	Exon 11 of 11	1	NM_003586.3	ENSP00000340017.4		Q14183-1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000127

AC:

AN:

244148

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

132594

show subpopulations

Gnomad AFR exome

AF:

0.0000637

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000218

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000190

AC:

277

AN:

1458844

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

725802

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000225

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000210

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1090G>A (p.E364K) 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 1090, causing the glutamic acid (E) at amino acid position 364 to be replaced by a lysine (K). 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

0.26

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;T;T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;D;.;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.6

L;L;L;L

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;.;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.024

D;.;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.29

MVP

0.78

MPC

0.50

ClinPred

0.072

GERP RS

5.6

Varity_R

0.40

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over