16-30006262-G-A

Variant names:

• chr16-30006262-G-A
• rs34246709
• NM_003586.3:c.1127C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P376A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (6 hom.)
• Consequence: DOC2A NM_003586.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.00
• Publications: 1 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: Benign. The variant received -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 VariationId is 725630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1127C>T	p.Pro376Leu	missense	Exon 11 of 11	NP_003577.2
	DOC2A	NM_001282062.1		c.1127C>T	p.Pro376Leu	missense	Exon 12 of 12	NP_001268991.1	Q14183-1
	DOC2A	NM_001282063.2		c.1127C>T	p.Pro376Leu	missense	Exon 12 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.1127C>T	p.Pro376Leu	missense	Exon 11 of 11	ENSP00000340017.4	Q14183-1
	DOC2A	ENST00000564979.5	TSL:1	c.1127C>T	p.Pro376Leu	missense	Exon 11 of 11	ENSP00000455624.1	Q14183-1
	DOC2A	ENST00000616445.4	TSL:1	c.1127C>T	p.Pro376Leu	missense	Exon 12 of 12	ENSP00000482870.1	Q14183-1

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 603 AN: 152030 Hom.: 7 Cov.: 31

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

GnomAD2 exomes AF: 0.00133 AC: 295 AN: 221406 AF XY: 0.00108

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 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.: 6 Cov.: 32 AF XY: 0.000701 AC XY: 504 AN XY: 719478

African (AFR) AF: 0.0155 AC: 517 AN: 33248

American (AMR) AF: 0.00124 AC: 52 AN: 41934

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 44 AN: 25792

East Asian (EAS) AF: 0.0000767 AC: 3 AN: 39130

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51134

Middle Eastern (MID) AF: 0.00165 AC: 9 AN: 5460

European-Non Finnish (NFE) AF: 0.000348 AC: 385 AN: 1106272

Other (OTH) AF: 0.00124 AC: 74 AN: 59834

GnomAD4 genome AF: 0.00400 AC: 608 AN: 152148 Hom.: 7 Cov.: 31 AF XY: 0.00375 AC XY: 279 AN XY: 74378

African (AFR) AF: 0.0132 AC: 550 AN: 41510

American (AMR) AF: 0.00183 AC: 28 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67962

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00211 Hom.: 12

Bravo AF: 0.00456

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0144 AC: 63

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00160 AC: 193

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Benign	0.13	T
Sift4G	Uncertain	0.048	D
Polyphen		0.11	B
Vest4		0.097
MVP		0.58
MPC		0.38
ClinPred		0.025	T
GERP RS		0.24
Varity_R		0.041
gMVP		0.37
Mutation Taster		=98/2	polymorphism

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: rs34246709; hg19: chr16-30017583;