rs17698193

Positions:

• chr2-70662366-A-G

Variant summary

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

The NM_001617.4(ADD2):​c.*1059T>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 0.198 in 152,122 control chromosomes in the GnomAD database, including 3,082 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 0.20 (3082 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: ADD2 NM_001617.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADD2	NM_001617.4	c.*1059T>C		3_prime_UTR_variant	16/16	ENST00000264436.9	NP_001608.1
ADD2	NM_001185054.2	c.*1059T>C		3_prime_UTR_variant	16/16		NP_001171983.1
ADD2	NM_017488.4	c.*1394T>C		3_prime_UTR_variant	17/17		NP_059522.1
ADD2	XM_011532502.3	c.*1059T>C		3_prime_UTR_variant	16/16		XP_011530804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADD2	ENST00000264436.9	c.*1059T>C		3_prime_UTR_variant	16/16	1	NM_001617.4	ENSP00000264436.3
ADD2	ENST00000407644.6	c.*1059T>C		3_prime_UTR_variant	16/16	1		ENSP00000384677.2
ADD2	ENST00000403045.6	n.*181+878T>C		intron_variant		2		ENSP00000384303.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30040 AN: 151974 Hom.: 3081 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.167 AC: 5 AN: 30 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 4 AN XY: 24

Gnomad4 AFR exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.198 AC: 30076 AN: 152092 Hom.: 3082 Cov.: 32 AF XY: 0.202 AC XY: 15049 AN XY: 74340

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.209

Alfa AF: 0.188 Hom.: 4019

Bravo AF: 0.190

Asia WGS AF: 0.246 AC: 854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.1
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs17698193; hg19: chr2-70889498;