NM_000686.5:c.402dupT

Variant names:

• chrX-116172674-A-AT
• rs387906503
• NM_000686.5:c.402dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000686.5(AGTR2):​c.402dupT​(p.Ile135TyrfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000441 in 1,208,111 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 162 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00045 (0 hom. 153 hem.)
• Consequence: AGTR2 NM_000686.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000686.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	NM_000686.5	MANE Select	c.402dupT	p.Ile135TyrfsTer7	frameshift	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.402dupT	p.Ile135TyrfsTer7	frameshift	Exon 2 of 2	NP_001372553.1	P50052

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	ENST00000371906.5	TSL:1 MANE Select	c.402dupT	p.Ile135TyrfsTer7	frameshift	Exon 3 of 3	ENSP00000360973.4	P50052
	AGTR2	ENST00000681852.1		c.402dupT	p.Ile135TyrfsTer7	frameshift	Exon 2 of 2	ENSP00000505750.1	P50052
	AGTR2	ENST00000971224.1		c.402dupT	p.Ile135TyrfsTer7	frameshift	Exon 3 of 3	ENSP00000641283.1

Frequencies

GnomAD3 genomes AF: 0.000353 AC: 39 AN: 110551 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000774

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: 0.000530

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 64 AN: 182958 AF XY: 0.000370

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000576

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000450 AC: 494 AN: 1097560 Hom.: 0 Cov.: 31 AF XY: 0.000421 AC XY: 153 AN XY: 363022

African (AFR) AF: 0.000265 AC: 7 AN: 26382

American (AMR) AF: 0.000256 AC: 9 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19372

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30195

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54129

European-Finnish (FIN) AF: 0.0000740 AC: 3 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.000534 AC: 449 AN: 841556

Other (OTH) AF: 0.000326 AC: 15 AN: 46076

GnomAD4 genome AF: 0.000353 AC: 39 AN: 110551 Hom.: 0 Cov.: 23 AF XY: 0.000274 AC XY: 9 AN XY: 32889

African (AFR) AF: 0.0000989 AC: 3 AN: 30337

American (AMR) AF: 0.000774 AC: 8 AN: 10337

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5899

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000530 AC: 28 AN: 52815

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.000442

EpiCase AF: 0.000764

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=169/31	polymorphism

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

Other links and lift over

dbSNP: rs387906503; hg19: chrX-115303927; COSMIC: COSV64156750;