2-70709729-T-C

Variant names:

• chr2-70709729-T-C
• rs3771452
• NM_001617.4:c.-34-3287A>G

Variant summary

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

The NM_001617.4(ADD2):​c.-34-3287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 152,150 control chromosomes in the GnomAD database, including 33,279 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 0.66 (33279 hom., cov: 32)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD2	NM_001617.4	c.-34-3287A>G		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.-34-3287A>G		intron_variant	Intron 2 of 15	1	NM_001617.4	ENSP00000264436.3

Frequencies

GnomAD3 genomes AF: 0.658 AC: 100092 AN: 152032 Hom.: 33235 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.641

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

GnomAD4 genome AF: 0.659 AC: 100206 AN: 152150 Hom.: 33279 Cov.: 32 AF XY: 0.652 AC XY: 48460 AN XY: 74362

African (AFR) AF: 0.753 AC: 31276 AN: 41530

American (AMR) AF: 0.640 AC: 9790 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2435 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2985 AN: 5172

South Asian (SAS) AF: 0.596 AC: 2872 AN: 4820

European-Finnish (FIN) AF: 0.508 AC: 5366 AN: 10570

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43437 AN: 67982

Other (OTH) AF: 0.641 AC: 1356 AN: 2114

Alfa AF: 0.647 Hom.: 127588

Bravo AF: 0.673

Asia WGS AF: 0.624 AC: 2171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.71
PhyloP100		-1.8
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: rs3771452; hg19: chr2-70936861;