2-70663688-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001617.4(ADD2):​c.1918G>A​(p.Glu640Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

ADD2
NM_001617.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.765
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.038292557).
BS2
High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADD2NM_001617.4 linkc.1918G>A p.Glu640Lys missense_variant Exon 16 of 16 ENST00000264436.9 NP_001608.1 P35612-1Q05DK5
ADD2NM_001185054.2 linkc.1918G>A p.Glu640Lys missense_variant Exon 16 of 16 NP_001171983.1 P35612-1Q05DK5
ADD2XM_011532502.3 linkc.1918G>A p.Glu640Lys missense_variant Exon 16 of 16 XP_011530804.1 P35612-1
ADD2NM_017488.4 linkc.*72G>A 3_prime_UTR_variant Exon 17 of 17 NP_059522.1 P35612-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADD2ENST00000264436.9 linkc.1918G>A p.Glu640Lys missense_variant Exon 16 of 16 1 NM_001617.4 ENSP00000264436.3 P35612-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248768
Hom.:
0
AF XY:
0.0000743
AC XY:
10
AN XY:
134654
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000900
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461878
Hom.:
1
Cov.:
31
AF XY:
0.0000399
AC XY:
29
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000351
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000555
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 04, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1918G>A (p.E640K) alteration is located in exon 16 (coding exon 14) of the ADD2 gene. This alteration results from a G to A substitution at nucleotide position 1918, causing the glutamic acid (E) at amino acid position 640 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
12
DANN
Benign
0.68
DEOGEN2
Benign
0.096
T;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.65
.;T
M_CAP
Benign
0.0049
T
MetaRNN
Benign
0.038
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.8
L;L
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.41
N;N
REVEL
Benign
0.023
Sift
Benign
0.86
T;T
Sift4G
Benign
0.71
T;T
Polyphen
0.0020
B;B
Vest4
0.050
MutPred
0.17
Gain of ubiquitination at E640 (P = 0.0037);Gain of ubiquitination at E640 (P = 0.0037);
MVP
0.22
MPC
0.53
ClinPred
0.025
T
GERP RS
2.4
Varity_R
0.019
gMVP
0.12

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781794877; hg19: chr2-70890820; COSMIC: COSV52456514; API