NM_000683.4:c.971_982delGGCCGGGGGCGG

Variant names:

• chr4-3767568-AGGGGGCGGGGCC-A
• rs61767072
• NM_000683.4:c.971_982delGGCCGGGGGCGG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BA1

The NM_000683.4(ADRA2C):​c.971_982delGGCCGGGGGCGG​(p.Gly324_Ala327del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0809 in 1,097,418 control chromosomes in the GnomAD database, including 7,623 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. G324G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (3700 hom., cov: 30)
  • Exomes 𝑓: 0.069 (3923 hom.)
• Consequence: ADRA2C NM_000683.4 disruptive_inframe_deletion
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.45
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000683.4.
• BP6: Variant 4-3767568-AGGGGGCGGGGCC-A is Benign according to our data. Variant chr4-3767568-AGGGGGCGGGGCC-A is described in ClinVar as Benign. ClinVar VariationId is 18160.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA2C	NM_000683.4	c.971_982delGGCCGGGGGCGG	p.Gly324_Ala327del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000330055.7	NP_000674.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA2C	ENST00000330055.7	c.971_982delGGCCGGGGGCGG	p.Gly324_Ala327del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_000683.4	ENSP00000386069.2
ADRA2C	ENST00000509482.1	c.971_982delGGCCGGGGGCGG	p.Gly324_Ala327del	disruptive_inframe_deletion	Exon 1 of 2	3		ENSP00000426268.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23104 AN: 146708 Hom.: 3683 Cov.: 30

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0923

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.122 AC: 21 AN: 172 AF XY: 0.130

Gnomad NFE exome AF: 0.115

GnomAD4 exome AF: 0.0691 AC: 65644 AN: 950608 Hom.: 3923 AF XY: 0.0693 AC XY: 31127 AN XY: 449120

African (AFR) AF: 0.454 AC: 9294 AN: 20460

American (AMR) AF: 0.0979 AC: 558 AN: 5700

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 968 AN: 10670

East Asian (EAS) AF: 0.103 AC: 1968 AN: 19126

South Asian (SAS) AF: 0.150 AC: 3010 AN: 20006

European-Finnish (FIN) AF: 0.0154 AC: 262 AN: 16962

Middle Eastern (MID) AF: 0.161 AC: 400 AN: 2482

European-Non Finnish (NFE) AF: 0.0556 AC: 45485 AN: 818380

Other (OTH) AF: 0.100 AC: 3699 AN: 36822

GnomAD4 genome AF: 0.158 AC: 23153 AN: 146810 Hom.: 3700 Cov.: 30 AF XY: 0.155 AC XY: 11106 AN XY: 71550

African (AFR) AF: 0.408 AC: 16625 AN: 40718

American (AMR) AF: 0.0923 AC: 1366 AN: 14802

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 259 AN: 3394

East Asian (EAS) AF: 0.122 AC: 614 AN: 5036

South Asian (SAS) AF: 0.128 AC: 612 AN: 4792

European-Finnish (FIN) AF: 0.0118 AC: 103 AN: 8724

Middle Eastern (MID) AF: 0.133 AC: 38 AN: 286

European-Non Finnish (NFE) AF: 0.0494 AC: 3263 AN: 66110

Other (OTH) AF: 0.132 AC: 270 AN: 2040

Alfa AF: 0.113 Hom.: 279

Bravo AF: 0.168

Asia WGS AF: 0.117 AC: 372 AN: 3168

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:1

Apr 01, 2007

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=189/11	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61767072; hg19: chr4-3769295;