rs2072246

Variant names:

• chr2-70693049-C-T
• rs2072246
• NM_001617.4:c.556-497G>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.556-497G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 151,910 control chromosomes in the GnomAD database, including 6,731 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 0.29 (6731 hom., cov: 31)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.302
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 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.556-497G>A		intron	N/A	NP_001608.1	P35612-1
	ADD2	NM_001185054.2		c.556-497G>A		intron	N/A	NP_001171983.1	P35612-1
	ADD2	NM_017488.4		c.556-497G>A		intron	N/A	NP_059522.1	P35612-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD2	ENST00000264436.9	TSL:1 MANE Select	c.556-497G>A		intron	N/A	ENSP00000264436.3	P35612-1
	ADD2	ENST00000407644.6	TSL:1	c.556-497G>A		intron	N/A	ENSP00000384677.2	P35612-1
	ADD2	ENST00000355733.7	TSL:1	c.556-497G>A		intron	N/A	ENSP00000347972.3	P35612-3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43988 AN: 151792 Hom.: 6722 Cov.: 31

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.267

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

GnomAD4 genome AF: 0.290 AC: 44061 AN: 151910 Hom.: 6731 Cov.: 31 AF XY: 0.291 AC XY: 21582 AN XY: 74256

African (AFR) AF: 0.384 AC: 15882 AN: 41388

American (AMR) AF: 0.254 AC: 3886 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3470

East Asian (EAS) AF: 0.438 AC: 2259 AN: 5162

South Asian (SAS) AF: 0.323 AC: 1555 AN: 4810

European-Finnish (FIN) AF: 0.242 AC: 2563 AN: 10574

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16286 AN: 67926

Other (OTH) AF: 0.270 AC: 568 AN: 2100

Alfa AF: 0.265 Hom.: 685

Bravo AF: 0.296

Asia WGS AF: 0.377 AC: 1308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.25
PhyloP100		-0.30
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: rs2072246; hg19: chr2-70920181;