rs2270042

Variant names:

• chr2-70687913-T-C
• rs2270042
• NM_001617.4:c.948+111A>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.948+111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 729,222 control chromosomes in the GnomAD database, including 26,537 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 (6764 hom., cov: 33)
  • Exomes 𝑓: 0.26 (19773 hom.)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• 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]

ENSG00000235035 (HGNC:40065):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD2	NM_001617.4	MANE Select	c.948+111A>G		intron	N/A	NP_001608.1
	ADD2	NM_001185054.2		c.948+111A>G		intron	N/A	NP_001171983.1
	ADD2	NM_017488.4		c.948+111A>G		intron	N/A	NP_059522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD2	ENST00000264436.9	TSL:1 MANE Select	c.948+111A>G		intron	N/A	ENSP00000264436.3
	ADD2	ENST00000407644.6	TSL:1	c.948+111A>G		intron	N/A	ENSP00000384677.2
	ADD2	ENST00000355733.7	TSL:1	c.948+111A>G		intron	N/A	ENSP00000347972.3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44034 AN: 152030 Hom.: 6755 Cov.: 33

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.270

GnomAD4 exome AF: 0.256 AC: 147819 AN: 577074 Hom.: 19773 AF XY: 0.259 AC XY: 79141 AN XY: 305410

African (AFR) AF: 0.391 AC: 5749 AN: 14688

American (AMR) AF: 0.250 AC: 6086 AN: 24336

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 3378 AN: 15770

East Asian (EAS) AF: 0.378 AC: 12351 AN: 32640

South Asian (SAS) AF: 0.326 AC: 16760 AN: 51346

European-Finnish (FIN) AF: 0.231 AC: 10966 AN: 47402

Middle Eastern (MID) AF: 0.318 AC: 781 AN: 2458

European-Non Finnish (NFE) AF: 0.233 AC: 83629 AN: 358158

Other (OTH) AF: 0.268 AC: 8119 AN: 30276

GnomAD4 genome AF: 0.290 AC: 44107 AN: 152148 Hom.: 6764 Cov.: 33 AF XY: 0.291 AC XY: 21623 AN XY: 74384

African (AFR) AF: 0.385 AC: 15965 AN: 41500

American (AMR) AF: 0.254 AC: 3884 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3470

East Asian (EAS) AF: 0.438 AC: 2265 AN: 5174

South Asian (SAS) AF: 0.322 AC: 1554 AN: 4824

European-Finnish (FIN) AF: 0.242 AC: 2559 AN: 10596

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16252 AN: 67994

Other (OTH) AF: 0.274 AC: 577 AN: 2106

Alfa AF: 0.257 Hom.: 1032

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	-0.91
CADD	Benign	0.0040
DANN	Benign	0.43
PhyloP100		-1.4
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: rs2270042; hg19: chr2-70915045;