2-70710347-A-G

Variant names:

• chr2-70710347-A-G
• rs2024458
• NM_001617.4:c.-35+2719T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001617.4(ADD2):​c.-35+2719T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,160 control chromosomes in the GnomAD database, including 13,872 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 0.39 (13872 hom., cov: 33)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108
• Publications: 3 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD2	NM_001617.4	c.-35+2719T>C		intron_variant	Intron 2 of 15	ENST00000264436.9	NP_001608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD2	ENST00000264436.9	c.-35+2719T>C		intron_variant	Intron 2 of 15	1	NM_001617.4	ENSP00000264436.3

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59586 AN: 152042 Hom.: 13835 Cov.: 33

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.392 AC: 59686 AN: 152160 Hom.: 13872 Cov.: 33 AF XY: 0.392 AC XY: 29144 AN XY: 74388

African (AFR) AF: 0.661 AC: 27452 AN: 41524

American (AMR) AF: 0.353 AC: 5401 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3472

East Asian (EAS) AF: 0.449 AC: 2321 AN: 5174

South Asian (SAS) AF: 0.355 AC: 1714 AN: 4826

European-Finnish (FIN) AF: 0.281 AC: 2972 AN: 10572

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17837 AN: 67986

Other (OTH) AF: 0.362 AC: 763 AN: 2110

Alfa AF: 0.147 Hom.: 306

Bravo AF: 0.410

Asia WGS AF: 0.422 AC: 1465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.56
PhyloP100		-0.11
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: rs2024458; hg19: chr2-70937479;