2-70708095-A-T

Variant names:

• chr2-70708095-A-T
• rs1541582
• NM_001617.4:c.-34-1653T>A

Variant summary

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

The NM_001617.4(ADD2):​c.-34-1653T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,002 control chromosomes in the GnomAD database, including 13,026 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 0.38 (13026 hom., cov: 33)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.577
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001617.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD2	NM_001617.4	MANE Select	c.-34-1653T>A		intron	N/A	NP_001608.1
	ADD2	NM_001185054.2		c.-34-1653T>A		intron	N/A	NP_001171983.1
	ADD2	NM_017488.4		c.-34-1653T>A		intron	N/A	NP_059522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD2	ENST00000264436.9	TSL:1 MANE Select	c.-34-1653T>A		intron	N/A	ENSP00000264436.3
	ADD2	ENST00000407644.6	TSL:1	c.-34-1653T>A		intron	N/A	ENSP00000384677.2
	ADD2	ENST00000355733.7	TSL:1	c.-34-1653T>A		intron	N/A	ENSP00000347972.3

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58386 AN: 151884 Hom.: 12988 Cov.: 33

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.385 AC: 58487 AN: 152002 Hom.: 13026 Cov.: 33 AF XY: 0.385 AC XY: 28591 AN XY: 74282

African (AFR) AF: 0.629 AC: 26097 AN: 41472

American (AMR) AF: 0.352 AC: 5383 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 941 AN: 3468

East Asian (EAS) AF: 0.448 AC: 2301 AN: 5136

South Asian (SAS) AF: 0.357 AC: 1718 AN: 4810

European-Finnish (FIN) AF: 0.282 AC: 2986 AN: 10580

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18017 AN: 67952

Other (OTH) AF: 0.358 AC: 753 AN: 2106

Alfa AF: 0.155 Hom.: 251

Bravo AF: 0.402

Asia WGS AF: 0.421 AC: 1460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.1
DANN	Benign	0.70
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1541582; hg19: chr2-70935227;