chr16-30006638-C-G

Variant names:

• chr16-30006638-C-G
• rs1231024377
• NM_003586.3:c.918G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003586.3(DOC2A):​c.918G>C​(p.Lys306Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DOC2A NM_003586.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOC2A	NM_003586.3	MANE Select	c.918G>C	p.Lys306Asn	missense	Exon 9 of 11	NP_003577.2
	DOC2A	NM_001282062.1		c.918G>C	p.Lys306Asn	missense	Exon 10 of 12	NP_001268991.1	Q14183-1
	DOC2A	NM_001282063.2		c.918G>C	p.Lys306Asn	missense	Exon 10 of 12	NP_001268992.1	Q14183-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOC2A	ENST00000350119.9	TSL:1 MANE Select	c.918G>C	p.Lys306Asn	missense	Exon 9 of 11	ENSP00000340017.4	Q14183-1
	DOC2A	ENST00000564979.5	TSL:1	c.918G>C	p.Lys306Asn	missense	Exon 9 of 11	ENSP00000455624.1	Q14183-1
	DOC2A	ENST00000616445.4	TSL:1	c.918G>C	p.Lys306Asn	missense	Exon 10 of 12	ENSP00000482870.1	Q14183-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151682 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 39 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151682 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74048

African (AFR) AF: 0.00 AC: 0 AN: 41244

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.40
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.68		Loss of methylation at K306 (P = 0.0255)
MVP		0.74
MPC		1.2
ClinPred		1.0	D
GERP RS		-2.3
Varity_R		0.70
gMVP		0.75

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

Other links and lift over

dbSNP: rs1231024377; hg19: chr16-30017959;