Genetic Variant DOC2A:p.Pro392Ala (chr16-30006215-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003586.3(DOC2A):c.1174C>G(p.Pro392Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,588,566 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0099 ( 108 hom. )

Consequence

DOC2A
NM_003586.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.314

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005557567).

BP6

Variant 16-30006215-G-C is Benign according to our data. Variant chr16-30006215-G-C is described in ClinVar as [Benign]. Clinvar id is 770252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOC2A	NM_003586.3 link	c.1174C>G	p.Pro392Ala	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.1174C>G	p.Pro392Ala	missense_variant	Exon 11 of 11	1	NM_003586.3	ENSP00000340017.4		Q14183-1

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

891

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00512

AC:

1050

AN:

204924

Hom.:

AF XY:

0.00492

AC XY:

548

AN XY:

111480

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.00374

Gnomad ASJ exome

AF:

0.00154

Gnomad EAS exome

AF:

0.0000652

Gnomad SAS exome

AF:

0.000772

Gnomad FIN exome

AF:

0.000811

Gnomad NFE exome

AF:

0.00943

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00993

AC:

14257

AN:

1436352

Hom.:

108

Cov.:

AF XY:

0.00948

AC XY:

6756

AN XY:

712682

show subpopulations

Gnomad4 AFR exome

AF:

0.00157

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.000933

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00967

GnomAD4 genome

AF:

0.00585

AC:

891

AN:

152214

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

386

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00823

Hom.:

Bravo

AF:

0.00604

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000688

AC:

ESP6500EA

AF:

0.00853

AC:

ExAC

AF:

0.00446

AC:

538

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

8.4

DANN

Benign

0.56

DEOGEN2

Benign

0.053

T;T;T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.61

.;T;.;.

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.83

L;L;L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.27

N;.;N;N

REVEL

Benign

0.075

Sift

Benign

0.51

T;.;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.52

P;P;P;P

Vest4

0.20

MVP

0.52

MPC

0.36

ClinPred

0.018

GERP RS

1.9

Varity_R

0.050

gMVP

0.13

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.

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