X-116172511-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000686.5(AGTR2):c.231G>T(p.Lys77Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,209,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00033 (0 hom. 111 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14683387).
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR2	NM_000686.5	c.231G>T	p.Lys77Asn	missense_variant	3/3	ENST00000371906.5
AGTR2	NM_001385624.1	c.231G>T	p.Lys77Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR2	ENST00000371906.5	c.231G>T	p.Lys77Asn	missense_variant	3/3	1	NM_000686.5	P1
AGTR2	ENST00000681852.1	c.231G>T	p.Lys77Asn	missense_variant	2/2			P1
AGTR2	ENST00000680409.1	n.699G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000242 AC: 27 AN: 111428 Hom.: 0 Cov.: 23 AF XY: 0.000119 AC XY: 4 AN XY: 33658

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000960

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: 0.000377

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 40 AN: 182847 Hom.: 0 AF XY: 0.000267 AC XY: 18 AN XY: 67535

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000418

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000328 AC: 360 AN: 1098005 Hom.: 0 Cov.: 31 AF XY: 0.000305 AC XY: 111 AN XY: 363445

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.000260

GnomAD4 genome AF: 0.000242 AC: 27 AN: 111428 Hom.: 0 Cov.: 23 AF XY: 0.000119 AC XY: 4 AN XY: 33658

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.0000960

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000377

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000406 Hom.: 13

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000546

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 22, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.14
Sift	Benign	0.072	T
Sift4G	Benign	0.14	T
Polyphen		0.81	P
Vest4		0.20
MutPred		0.60		Loss of methylation at K77 (P = 0.0075);
MVP		0.79
MPC		0.45
ClinPred		0.067	T
GERP RS		2.5
Varity_R		0.42
gMVP		0.28

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: rs138706948; hg19: chrX-115303764;