chr2-70674792-C-T

Variant names:

• chr2-70674792-C-T
• rs139586218
• NM_001617.4:c.1627G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001617.4(ADD2):​c.1627G>A​(p.Glu543Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,104 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: ADD2 NM_001617.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.331
• Publications: 4 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]

LOC105374794 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022371411).
• BP6: Variant 2-70674792-C-T is Benign according to our data. Variant chr2-70674792-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2651015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 196 AD gene.

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.1627G>A	p.Glu543Lys	missense	Exon 14 of 16	NP_001608.1	P35612-1
	ADD2	NM_001185054.2		c.1627G>A	p.Glu543Lys	missense	Exon 14 of 16	NP_001171983.1	P35612-1
	ADD2	NM_017488.4		c.1627G>A	p.Glu543Lys	missense	Exon 14 of 17	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.1627G>A	p.Glu543Lys	missense	Exon 14 of 16	ENSP00000264436.3	P35612-1
	ADD2	ENST00000407644.6	TSL:1	c.1627G>A	p.Glu543Lys	missense	Exon 14 of 16	ENSP00000384677.2	P35612-1
	ADD2	ENST00000355733.7	TSL:1	c.1627G>A	p.Glu543Lys	missense	Exon 14 of 17	ENSP00000347972.3	P35612-3

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00164 AC: 411 AN: 251360 AF XY: 0.00160

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000651

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00123 AC: 1794 AN: 1461830 Hom.: 17 Cov.: 31 AF XY: 0.00129 AC XY: 938 AN XY: 727222

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 890 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000641 AC: 713 AN: 1111972

Other (OTH) AF: 0.00260 AC: 157 AN: 60396

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74456

African (AFR) AF: 0.000217 AC: 9 AN: 41560

American (AMR) AF: 0.00163 AC: 25 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00205 Hom.: 15

Bravo AF: 0.00134

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00119 AC: 144

EpiCase AF: 0.00175

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.33
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.076
Sift	Benign	0.36	T
Sift4G	Benign	0.90	T
Polyphen		0.0030	B
Vest4		0.071
MVP		0.33
MPC		0.49
ClinPred		0.020	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.34
Mutation Taster		=100/0	polymorphism

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: rs139586218; hg19: chr2-70901924;