4-3766653-C-T

Position:

• chr4-3766653-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000683.4(ADRA2C):​c.47C>T​(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ADRA2C NM_000683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.820

Genes affected

ADRA2C (HGNC:283): (adrenoceptor alpha 2C) Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. The mouse studies revealed that both the alpha2A and alpha2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. The alpha2A subtype inhibited transmitter release at high stimulation frequencies, whereas the alpha2C subtype modulated neurotransmission at lower levels of nerve activity. This gene encodes the alpha2C subtype, which contains no introns in either its coding or untranslated sequences. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06904015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRA2C	NM_000683.4	c.47C>T	p.Ala16Val	missense_variant	1/1	ENST00000330055.7	NP_000674.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRA2C	ENST00000330055.7	c.47C>T	p.Ala16Val	missense_variant	1/1	6	NM_000683.4	ENSP00000386069.2
ADRA2C	ENST00000509482.1	c.47C>T	p.Ala16Val	missense_variant	1/2	3		ENSP00000426268.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1089368 Hom.: 0 Cov.: 30 AF XY: 0.00000388 AC XY: 2 AN XY: 515860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000471

Gnomad4 FIN exome AF: 0.0000442

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.47C>T (p.A16V) alteration is located in exon 1 (coding exon 1) of the ADRA2C gene. This alteration results from a C to T substitution at nucleotide position 47, causing the alanine (A) at amino acid position 16 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.032
Sift	Benign	0.074	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.0010	B;B
Vest4		0.12
MutPred		0.25		Gain of catalytic residue at A16 (P = 0.0078);Gain of catalytic residue at A16 (P = 0.0078);
MVP		0.45
ClinPred		0.050	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.041
gMVP		0.21

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

Other links and lift over

dbSNP: rs1735448256; hg19: chr4-3768380;