rs4984

Positions:

• chr2-70673271-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000355733.7(ADD2):​c.1797C>T​(p.Ser599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,613,672 control chromosomes in the GnomAD database, including 13,243 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 0.15 (1862 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11381 hom.)
• Consequence: ADD2 ENST00000355733.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

Genes affected

ADD2 (HGNC:244): (adducin 2) Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jun 2010]

LOC105374794 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD2	NM_001617.4	c.1742-265C>T		intron_variant		ENST00000264436.9
LOC105374794	XR_940230.3	n.17G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD2	ENST00000264436.9	c.1742-265C>T		intron_variant		1	NM_001617.4	P2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22581 AN: 151866 Hom.: 1857 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.00639

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.120 AC: 30141 AN: 251416 Hom.: 2116 AF XY: 0.118 AC XY: 15974 AN XY: 135884

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.00343

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.121 AC: 176188 AN: 1461690 Hom.: 11381 Cov.: 31 AF XY: 0.120 AC XY: 87101 AN XY: 727158

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.00214

Gnomad4 SAS exome AF: 0.0983

Gnomad4 FIN exome AF: 0.0998

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.149 AC: 22618 AN: 151982 Hom.: 1862 Cov.: 32 AF XY: 0.146 AC XY: 10815 AN XY: 74282

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.00602

Gnomad4 SAS AF: 0.0936

Gnomad4 FIN AF: 0.0975

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.166

Alfa AF: 0.137 Hom.: 849

Bravo AF: 0.158

Asia WGS AF: 0.0780 AC: 269 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.132

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.49

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: rs4984; hg19: chr2-70900403;