rs4984

Variant names:

• chr2-70673271-G-A
• rs4984
• ENST00000355733.7:c.1797C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000355733.7(ADD2):​c.1797C>T​(p.Ser599Ser) 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
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ADD2	NM_001617.4	c.1742-265C>T		intron_variant	Intron 14 of 15	ENST00000264436.9	NP_001608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD2	ENST00000264436.9	c.1742-265C>T		intron_variant	Intron 14 of 15	1	NM_001617.4	ENSP00000264436.3

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

GnomAD2 exomes AF: 0.120 AC: 30141 AN: 251416 AF XY: 0.118

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 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

African (AFR) AF: 0.231 AC: 7717 AN: 33470

American (AMR) AF: 0.143 AC: 6377 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4663 AN: 26136

East Asian (EAS) AF: 0.00214 AC: 85 AN: 39700

South Asian (SAS) AF: 0.0983 AC: 8479 AN: 86252

European-Finnish (FIN) AF: 0.0998 AC: 5330 AN: 53414

Middle Eastern (MID) AF: 0.132 AC: 760 AN: 5760

European-Non Finnish (NFE) AF: 0.121 AC: 135089 AN: 1111848

Other (OTH) AF: 0.127 AC: 7688 AN: 60390

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

African (AFR) AF: 0.226 AC: 9370 AN: 41410

American (AMR) AF: 0.162 AC: 2476 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3468

East Asian (EAS) AF: 0.00602 AC: 31 AN: 5152

South Asian (SAS) AF: 0.0936 AC: 451 AN: 4816

European-Finnish (FIN) AF: 0.0975 AC: 1031 AN: 10576

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8145 AN: 67972

Other (OTH) AF: 0.166 AC: 348 AN: 2102

Alfa AF: 0.138 Hom.: 1186

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
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs4984; hg19: chr2-70900403;