2-70674792-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/21 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

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

Verdict is Benign. Variant got -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 id is 2651015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD2	NM_001617.4	c.1627G>A	p.Glu543Lys	missense_variant	14/16	ENST00000264436.9
LOC105374794	XR_940230.3	n.125+1413C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD2	ENST00000264436.9	c.1627G>A	p.Glu543Lys	missense_variant	14/16	1	NM_001617.4	P2

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

GnomAD3 exomes AF: 0.00164 AC: 411 AN: 251360 Hom.: 6 AF XY: 0.00160 AC XY: 217 AN XY: 135842

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000641

Gnomad4 OTH exome AF: 0.00260

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

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.0325

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00221 Hom.: 11

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

ADD2: BP4 -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.90	T;T;T;.;.
Polyphen		0.0030	B;B;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

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: rs139586218; hg19: chr2-70901924;