rs13416248

chr2-70754321-C-T

Variant summary

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

The NM_001617.4(ADD2):c.-154+13565G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 151,984 control chromosomes in the GnomAD database, including 4,190 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 0.22 (4190 hom., cov: 31)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD2	NM_001617.4	c.-154+13565G>A		intron_variant		ENST00000264436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD2	ENST00000264436.9	c.-154+13565G>A		intron_variant		1	NM_001617.4	P2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33153 AN: 151866 Hom.: 4197 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33160 AN: 151984 Hom.: 4190 Cov.: 31 AF XY: 0.229 AC XY: 17035 AN XY: 74274

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.204

Alfa AF: 0.209 Hom.: 2589

Bravo AF: 0.212

Asia WGS AF: 0.355 AC: 1233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	13
Dann	Benign	0.73

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: rs13416248; hg19: chr2-70981453;