X-116172354-T-A

Position:

• chrX-116172354-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000686.5(AGTR2):​c.74T>A​(p.Ile25Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,557 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.450

Genes affected

AGTR2 (HGNC:338): (angiotensin II receptor type 2) The protein encoded by this gene belongs to the G-protein coupled receptor 1 family, and functions as a receptor for angiotensin II. It is an intergral membrane protein that is highly expressed in fetus and in neonates, but scantily in adult tissues, except brain, adrenal medulla, and atretic ovary. This receptor has been shown to mediate programmed cell death and this apoptotic function may play an important role in developmental biology and pathophysiology. Mutations in this gene are been associated with X-linked cognitive disability. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2 infection results in down-regulation of angiotensin converting enzyme-2 (ACE2) receptors, the effects of which, triggers serious inflammatory lesions in the tissues involved, primarily in the lungs. The inflammatory reaction appears to be mediated by angiotensin II derivatives, including the angiotensin AT2 receptor which has been found to be upregulated in bronchoalveolar lavage samples from Coronavirus disease 2019 (COVID19) patients. [provided by RefSeq, Jul 2020]

AGTR2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07319206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR2	NM_000686.5	c.74T>A	p.Ile25Asn	missense_variant	3/3	ENST00000371906.5	NP_000677.2
AGTR2	NM_001385624.1	c.74T>A	p.Ile25Asn	missense_variant	2/2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGTR2	ENST00000371906.5	c.74T>A	p.Ile25Asn	missense_variant	3/3	1	NM_000686.5	ENSP00000360973.4
AGTR2	ENST00000681852.1	c.74T>A	p.Ile25Asn	missense_variant	2/2			ENSP00000505750.1
AGTR2	ENST00000680409.1	n.542T>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097557 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363097

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: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

Nov 09, 2024

The c.74T>A (p.I25N) alteration is located in exon 3 (coding exon 1) of the AGTR2 gene. This alteration results from a T to A substitution at nucleotide position 74, causing the isoleucine (I) at amino acid position 25 to be replaced by an asparagine (N). 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	0.093
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.058
Sift	Benign	0.21	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.49		Gain of disorder (P = 0.0026);
MVP		0.57
MPC		0.25
ClinPred		0.020	T
GERP RS		1.6
Varity_R		0.051
gMVP		0.30

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: chrX-115303607;