2-70678913-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001617.4(ADD2):c.1174A>T(p.Thr392Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADD2 NM_001617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.327

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043573827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD2	NM_001617.4	c.1174A>T	p.Thr392Ser	missense_variant	11/16	ENST00000264436.9
LOC105374794	XR_940230.3	n.292-560T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD2	ENST00000264436.9	c.1174A>T	p.Thr392Ser	missense_variant	11/16	1	NM_001617.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

The c.1174A>T (p.T392S) alteration is located in exon 11 (coding exon 9) of the ADD2 gene. This alteration results from a A to T substitution at nucleotide position 1174, causing the threonine (T) at amino acid position 392 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.074	T;T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.044	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.32	N;N;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.28	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.50	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0020	B;B;B;.;.
Vest4		0.081
MutPred		0.22		Loss of phosphorylation at T392 (P = 0.0755);Loss of phosphorylation at T392 (P = 0.0755);Loss of phosphorylation at T392 (P = 0.0755);Loss of phosphorylation at T392 (P = 0.0755);.;
MVP		0.40
MPC		0.39
ClinPred		0.23	T
GERP RS		1.4
Varity_R		0.082
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-70906045;