2-70731034-C-T

Variant names:

• chr2-70731034-C-T
• rs12621522
• NM_001617.4:c.-153-17850G>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.-153-17850G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,058 control chromosomes in the GnomAD database, including 5,718 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 0.26 (5718 hom., cov: 32)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• 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 (EAS) allele frequency at 95% confidence interval = 0.55 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.-153-17850G>A		intron	N/A	NP_001608.1	P35612-1
	ADD2	NM_001185054.2		c.-153-17850G>A		intron	N/A	NP_001171983.1	P35612-1
	ADD2	NM_017488.4		c.-153-17850G>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.-153-17850G>A		intron	N/A	ENSP00000264436.3	P35612-1
	ADD2	ENST00000407644.6	TSL:1	c.-153-17850G>A		intron	N/A	ENSP00000384677.2	P35612-1
	ADD2	ENST00000355733.7	TSL:1	c.-153-17850G>A		intron	N/A	ENSP00000347972.3	P35612-3

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39679 AN: 151940 Hom.: 5723 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.244

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

GnomAD4 genome AF: 0.261 AC: 39696 AN: 152058 Hom.: 5718 Cov.: 32 AF XY: 0.272 AC XY: 20242 AN XY: 74322

African (AFR) AF: 0.283 AC: 11732 AN: 41472

American (AMR) AF: 0.259 AC: 3962 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 519 AN: 3472

East Asian (EAS) AF: 0.567 AC: 2928 AN: 5160

South Asian (SAS) AF: 0.397 AC: 1911 AN: 4814

European-Finnish (FIN) AF: 0.351 AC: 3706 AN: 10556

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.208 AC: 14161 AN: 67986

Other (OTH) AF: 0.246 AC: 519 AN: 2108

Alfa AF: 0.183 Hom.: 524

Bravo AF: 0.256

Asia WGS AF: 0.446 AC: 1552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.70
PhyloP100		-0.12
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: rs12621522; hg19: chr2-70958166;