Genetic Variant DOC2A:p.Pro376Leu (chr16-30006262-G-A) – 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.1127C>T(p.Pro376Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,599,830 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 7 hom., cov: 31)

Exomes 𝑓: 0.00075 ( 6 hom. )

Consequence

DOC2A
NM_003586.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.00

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=0.006090045).

BP6

Variant 16-30006262-G-A is Benign according to our data. Variant chr16-30006262-G-A is described in ClinVar as [Benign]. Clinvar id is 725630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOC2A	NM_003586.3 link	c.1127C>T	p.Pro376Leu	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.1127C>T	p.Pro376Leu	missense_variant	Exon 11 of 11	1	NM_003586.3	ENSP00000340017.4		Q14183-1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

603

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00133

AC:

295

AN:

221406

Hom.:

AF XY:

0.00108

AC XY:

130

AN XY:

120668

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.000933

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.0000610

Gnomad SAS exome

AF:

0.000139

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000419

Gnomad OTH exome

AF:

0.000542

GnomAD4 exome

AF:

0.000752

AC:

1089

AN:

1447682

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

504

AN XY:

719478

show subpopulations

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.00171

Gnomad4 EAS exome

AF:

0.0000767

Gnomad4 SAS exome

AF:

0.0000589

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000348

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00400

AC:

608

AN:

152148

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00456

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0144

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00160

AC:

193

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

- -

Jul 29, 2018

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

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Uncertain

0.44

T;T;T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.37

.;T;.;.

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.2

M;M;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;.;D;D

REVEL

Benign

0.19

Sift

Benign

0.13

T;.;T;T

Sift4G

Uncertain

0.048

D;D;D;D

Polyphen

0.11

B;B;B;B

Vest4

0.097

MVP

0.58

MPC

0.38

ClinPred

0.025

GERP RS

0.24

Varity_R

0.041

gMVP

0.37

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