X-116172594-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000686.5(AGTR2):c.314C>G(p.Ser105Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR2	NM_000686.5	c.314C>G	p.Ser105Cys	missense_variant	3/3	ENST00000371906.5
AGTR2	NM_001385624.1	c.314C>G	p.Ser105Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR2	ENST00000371906.5	c.314C>G	p.Ser105Cys	missense_variant	3/3	1	NM_000686.5	P1
AGTR2	ENST00000681852.1	c.314C>G	p.Ser105Cys	missense_variant	2/2			P1
AGTR2	ENST00000680409.1	n.782C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

Aug 12, 2021

The c.314C>G (p.S105C) alteration is located in exon 3 (coding exon 1) of the AGTR2 gene. This alteration results from a C to G substitution at nucleotide position 314, causing the serine (S) at amino acid position 105 to be replaced by a cysteine (C). 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	0.32
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.79		Gain of loop (P = 0.2045);
MVP		0.85
MPC		0.62
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.33

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: rs1922492079; hg19: chrX-115303847;