rs740387

Positions:

• chr2-70668767-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000264436.9(ADD2):​c.1870+4111A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,122 control chromosomes in the GnomAD database, including 1,984 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 0.15 (1984 hom., cov: 32)
• Consequence: ADD2 ENST00000264436.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADD2	NM_001617.4	c.1870+4111A>C		intron_variant		ENST00000264436.9	NP_001608.1
ADD2	NM_001185054.2	c.1870+4111A>C		intron_variant			NP_001171983.1
ADD2	NM_017488.4	c.*24+4111A>C		intron_variant			NP_059522.1
ADD2	XM_011532502.3	c.1870+4111A>C		intron_variant			XP_011530804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADD2	ENST00000264436.9	c.1870+4111A>C		intron_variant		1	NM_001617.4	ENSP00000264436	P2

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22918 AN: 152004 Hom.: 1970 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.00656

Gnomad SAS AF: 0.0941

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.151 AC: 22962 AN: 152122 Hom.: 1984 Cov.: 32 AF XY: 0.147 AC XY: 10962 AN XY: 74370

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.00619

Gnomad4 SAS AF: 0.0938

Gnomad4 FIN AF: 0.0979

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.157

Alfa AF: 0.129 Hom.: 365

Bravo AF: 0.160

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs740387; hg19: chr2-70895899;