NM_000686.5:c.402delT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000686.5(AGTR2):​c.402delT​(p.Phe134LeufsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000575 in 1,208,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 211 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00059 (0 hom. 200 hem.)
• Consequence: AGTR2 NM_000686.5 frameshift
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• 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: Benign. The variant received -12 ACMG points.

• BP6: Variant X-116172674-AT-A is Benign according to our data. Variant chrX-116172674-AT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 11717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 11 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.402delT	p.Phe134LeufsTer5	frameshift	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.402delT	p.Phe134LeufsTer5	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.402delT	p.Phe134LeufsTer5	frameshift	Exon 3 of 3	ENSP00000360973.4	P50052
	AGTR2	ENST00000681852.1		c.402delT	p.Phe134LeufsTer5	frameshift	Exon 2 of 2	ENSP00000505750.1	P50052
	AGTR2	ENST00000971224.1		c.402delT	p.Phe134LeufsTer5	frameshift	Exon 3 of 3	ENSP00000641283.1

Frequencies

GnomAD3 genomes AF: 0.000443 AC: 49 AN: 110551 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000833

Gnomad OTH AF: 0.000668

GnomAD2 exomes AF: 0.000454 AC: 83 AN: 182958 AF XY: 0.000414

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000589 AC: 646 AN: 1097460 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 200 AN XY: 362940

African (AFR) AF: 0.0000379 AC: 1 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40512

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

European-Non Finnish (NFE) AF: 0.000739 AC: 622 AN: 841467

Other (OTH) AF: 0.000391 AC: 18 AN: 46074

GnomAD4 genome AF: 0.000443 AC: 49 AN: 110602 Hom.: 0 Cov.: 23 AF XY: 0.000334 AC XY: 11 AN XY: 32950

African (AFR) AF: 0.000132 AC: 4 AN: 30402

American (AMR) AF: 0.00 AC: 0 AN: 10350

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3493

South Asian (SAS) AF: 0.00 AC: 0 AN: 2617

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000833 AC: 44 AN: 52807

Other (OTH) AF: 0.000659 AC: 1 AN: 1517

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.000461

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	AGTR2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=156/44	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: COSV64156240;