Genetic Variant DOC2A:p.Gly395Arg (chr16-30006206-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003586.3(DOC2A):c.1183G>C(p.Gly395Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DOC2A
NM_003586.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11400846).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOC2A	NM_003586.3	MANE Select	c.1183G>C	p.Gly395Arg	missense	Exon 11 of 11	NP_003577.2
DOC2A	NM_001282062.1		c.1183G>C	p.Gly395Arg	missense	Exon 12 of 12	NP_001268991.1	Q14183-1
DOC2A	NM_001282063.2		c.1183G>C	p.Gly395Arg	missense	Exon 12 of 12	NP_001268992.1	Q14183-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOC2A	ENST00000350119.9	TSL:1 MANE Select	c.1183G>C	p.Gly395Arg	missense	Exon 11 of 11	ENSP00000340017.4	Q14183-1
DOC2A	ENST00000564979.5	TSL:1	c.1183G>C	p.Gly395Arg	missense	Exon 11 of 11	ENSP00000455624.1	Q14183-1
DOC2A	ENST00000616445.4	TSL:1	c.1183G>C	p.Gly395Arg	missense	Exon 12 of 12	ENSP00000482870.1	Q14183-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710816

African (AFR)

AF:

0.00

AC:

AN:

33072

American (AMR)

AF:

0.00

AC:

AN:

39720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25530

East Asian (EAS)

AF:

0.00

AC:

AN:

38424

South Asian (SAS)

AF:

0.00

AC:

AN:

82890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099566

Other (OTH)

AF:

0.00

AC:

AN:

59240

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.054

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

PhyloP100

2.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.56

REVEL

Benign

0.089

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0090

Polyphen

0.012

Vest4

0.51

MutPred

0.24

Gain of methylation at G395 (P = 0.0212)

MVP

0.64

MPC

0.76

ClinPred

0.22

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over