chr2-70663664-C-A

Variant names:

• chr2-70663664-C-A
• rs1675629105
• NM_001617.4:c.1942G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001617.4(ADD2):​c.1942G>T​(p.Val648Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000041 (0 hom.)
• Consequence: ADD2 NM_001617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30401596).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD2	NM_001617.4	c.1942G>T	p.Val648Leu	missense_variant	Exon 16 of 16	ENST00000264436.9	NP_001608.1
ADD2	NM_001185054.2	c.1942G>T	p.Val648Leu	missense_variant	Exon 16 of 16		NP_001171983.1
ADD2	XM_011532502.3	c.1942G>T	p.Val648Leu	missense_variant	Exon 16 of 16		XP_011530804.1
ADD2	NM_017488.4	c.*96G>T		3_prime_UTR_variant	Exon 17 of 17		NP_059522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD2	ENST00000264436.9	c.1942G>T	p.Val648Leu	missense_variant	Exon 16 of 16	1	NM_001617.4	ENSP00000264436.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

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: 0.0000930 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1942G>T (p.V648L) alteration is located in exon 16 (coding exon 14) of the ADD2 gene. This alteration results from a G to T substitution at nucleotide position 1942, causing the valine (V) at amino acid position 648 to be replaced by a leucine (L). 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	0.17
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.16
Sift	Benign	0.51	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.99	D;D
Vest4		0.26
MutPred		0.28		Gain of catalytic residue at V648 (P = 0.0783);Gain of catalytic residue at V648 (P = 0.0783);
MVP		0.57
MPC		0.51
ClinPred		0.61	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.11

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: rs1675629105; hg19: chr2-70890796;