chr11-72239782-C-T

Variant names:

• chr11-72239782-C-T
• rs556502658
• NM_005169.4:c.822G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_005169.4(PHOX2A):​c.822G>A​(p.Lys274Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,331,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (2 hom.)
• Consequence: PHOX2A NM_005169.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0520
• Publications: 0 publications found

Genes affected

PHOX2A (HGNC:691): (paired like homeobox 2A) The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

PHOX2A Gene-Disease associations (from GenCC):

• fibrosis of extraocular muscles, congenital, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.102).
• BP6: Variant 11-72239782-C-T is Benign according to our data. Variant chr11-72239782-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 797504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005169.4. 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
	PHOX2A	NM_005169.4	MANE Select	c.822G>A	p.Lys274Lys	synonymous	Exon 3 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.906G>A	p.Lys302Lys	synonymous	Exon 3 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.846G>A	p.Lys282Lys	synonymous	Exon 3 of 3	NP_001412026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.822G>A	p.Lys274Lys	synonymous	Exon 3 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000546310.1	TSL:5	c.222G>A	p.Lys74Lys	synonymous	Exon 2 of 2	ENSP00000444845.1	H0YGU5
	PHOX2A	ENST00000544057.1	TSL:3	n.*85G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000556 AC: 5 AN: 89868 AF XY: 0.0000793

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000373 AC: 44 AN: 1178910 Hom.: 2 Cov.: 31 AF XY: 0.0000440 AC XY: 25 AN XY: 567748

African (AFR) AF: 0.00 AC: 0 AN: 25008

American (AMR) AF: 0.00 AC: 0 AN: 16962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15754

East Asian (EAS) AF: 0.00 AC: 0 AN: 30068

South Asian (SAS) AF: 0.000735 AC: 26 AN: 35354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40608

Middle Eastern (MID) AF: 0.000492 AC: 2 AN: 4068

European-Non Finnish (NFE) AF: 0.0000145 AC: 14 AN: 964242

Other (OTH) AF: 0.0000427 AC: 2 AN: 46846

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000331 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.7
DANN	Benign	0.95
PhyloP100		0.052
Mutation Taster		=100/0	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: rs556502658; hg19: chr11-71950826;