Genetic Variant NM_003586.3:c.793C>G (chr16-30006870-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003586.3(DOC2A):c.793C>G(p.Arg265Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DOC2A
NM_003586.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.82

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.793C>G	p.Arg265Gly	missense	Exon 8 of 11	NP_003577.2
DOC2A	NM_001282062.1		c.793C>G	p.Arg265Gly	missense	Exon 9 of 12	NP_001268991.1	Q14183-1
DOC2A	NM_001282063.2		c.793C>G	p.Arg265Gly	missense	Exon 9 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.793C>G	p.Arg265Gly	missense	Exon 8 of 11	ENSP00000340017.4	Q14183-1
DOC2A	ENST00000564979.5	TSL:1	c.793C>G	p.Arg265Gly	missense	Exon 8 of 11	ENSP00000455624.1	Q14183-1
DOC2A	ENST00000616445.4	TSL:1	c.793C>G	p.Arg265Gly	missense	Exon 9 of 12	ENSP00000482870.1	Q14183-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111756

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.5

PhyloP100

2.8

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.21

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.052

Polyphen

0.40

Vest4

0.52

MutPred

0.43

Loss of stability (P = 0.0137)

MVP

0.75

MPC

0.52

ClinPred

0.96

GERP RS

5.1

Varity_R

0.29

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