rs7434444

Positions:

• chr4-3768342-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000683.4(ADRA2C):​c.*347G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 714,670 control chromosomes in the GnomAD database, including 37,649 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (12820 hom., cov: 32)
  • Exomes 𝑓: 0.28 (24829 hom.)
• Consequence: ADRA2C NM_000683.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRA2C	NM_000683.4	c.*347G>C		3_prime_UTR_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.*347G>C		3_prime_UTR_variant	1/1	6	NM_000683.4	ENSP00000386069.2
ADRA2C	ENST00000509482.1	c.*67G>C		3_prime_UTR_variant	2/2	3		ENSP00000426268.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56179 AN: 151938 Hom.: 12787 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.283 AC: 159476 AN: 562614 Hom.: 24829 Cov.: 0 AF XY: 0.290 AC XY: 88088 AN XY: 303552

Gnomad4 AFR exome AF: 0.637

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.370 AC: 56270 AN: 152056 Hom.: 12820 Cov.: 32 AF XY: 0.373 AC XY: 27699 AN XY: 74342

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.313

Alfa AF: 0.327 Hom.: 1286

Bravo AF: 0.371

Asia WGS AF: 0.363 AC: 1263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.65

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: rs7434444; hg19: chr4-3770069; COSMIC: COSV57468107; COSMIC: COSV57468107;