4-41746494-T-G

Variant names:

• chr4-41746494-T-G
• rs2196822
• NM_003924.4:c.430-172A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003924.4(PHOX2B):​c.430-172A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,944 control chromosomes in the GnomAD database, including 12,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.37 (12099 hom., cov: 32)
• Consequence: PHOX2B NM_003924.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12
• Publications: 1 publications found

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

PHOX2B Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-41746494-T-G is Benign according to our data. Variant chr4-41746494-T-G is described in ClinVar as Benign. ClinVar VariationId is 1247551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. 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
	PHOX2B	NM_003924.4	MANE Select	c.430-172A>C		intron	N/A	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.430-172A>C		intron	N/A	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.251-172A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56272 AN: 151826 Hom.: 12082 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.319

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.371 AC: 56327 AN: 151944 Hom.: 12099 Cov.: 32 AF XY: 0.365 AC XY: 27135 AN XY: 74270

African (AFR) AF: 0.600 AC: 24850 AN: 41416

American (AMR) AF: 0.237 AC: 3627 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1184 AN: 3466

East Asian (EAS) AF: 0.179 AC: 921 AN: 5152

South Asian (SAS) AF: 0.383 AC: 1847 AN: 4820

European-Finnish (FIN) AF: 0.287 AC: 3028 AN: 10534

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19937 AN: 67958

Other (OTH) AF: 0.317 AC: 667 AN: 2104

Alfa AF: 0.174 Hom.: 348

Bravo AF: 0.375

Asia WGS AF: 0.298 AC: 1036 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.42
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2196822; hg19: chr4-41748511;