2-70747758-G-T

Variant names:

• chr2-70747758-G-T
• rs3755351
• NM_001617.4:c.-154+20128C>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.-154+20128C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,054 control chromosomes in the GnomAD database, including 8,753 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 0.34 (8753 hom., cov: 32)
• Consequence: ADD2 NM_001617.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487
• Publications: 8 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 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.-154+20128C>A		intron	N/A	NP_001608.1
	ADD2	NM_001185054.2		c.-154+19846C>A		intron	N/A	NP_001171983.1
	ADD2	NM_017488.4		c.-154+20128C>A		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.-154+20128C>A		intron	N/A	ENSP00000264436.3
	ADD2	ENST00000407644.6	TSL:1	c.-154+19846C>A		intron	N/A	ENSP00000384677.2
	ADD2	ENST00000355733.7	TSL:1	c.-154+20128C>A		intron	N/A	ENSP00000347972.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51374 AN: 151936 Hom.: 8749 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.338 AC: 51418 AN: 152054 Hom.: 8753 Cov.: 32 AF XY: 0.338 AC XY: 25099 AN XY: 74334

African (AFR) AF: 0.347 AC: 14384 AN: 41462

American (AMR) AF: 0.306 AC: 4678 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1340 AN: 3470

East Asian (EAS) AF: 0.333 AC: 1718 AN: 5160

South Asian (SAS) AF: 0.283 AC: 1366 AN: 4824

European-Finnish (FIN) AF: 0.347 AC: 3669 AN: 10576

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23040 AN: 67960

Other (OTH) AF: 0.374 AC: 789 AN: 2110

Alfa AF: 0.341 Hom.: 20408

Bravo AF: 0.338

Asia WGS AF: 0.322 AC: 1119 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.3
DANN	Benign	0.57
PhyloP100		0.49
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: rs3755351; hg19: chr2-70974890;