2-222231990-G-C

Variant names:

• chr2-222231990-G-C
• rs1965791
• NM_181458.4:c.792+88C>G

Variant summary

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

The NM_181458.4(PAX3):​c.792+88C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,208,638 control chromosomes in the GnomAD database, including 395,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46463 hom., cov: 32)
  • Exomes 𝑓: 0.80 (348616 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51
• Publications: 4 publications found

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 Gene-Disease associations (from GenCC):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-222231990-G-C is Benign according to our data. Variant chr2-222231990-G-C is described in ClinVar as Benign. ClinVar VariationId is 1278226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.792+88C>G		intron_variant	Intron 5 of 8	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.792+88C>G		intron_variant	Intron 5 of 8	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117741 AN: 152016 Hom.: 46449 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.775

GnomAD4 exome AF: 0.804 AC: 849519 AN: 1056504 Hom.: 348616 AF XY: 0.800 AC XY: 434976 AN XY: 544048

African (AFR) AF: 0.709 AC: 17972 AN: 25348

American (AMR) AF: 0.737 AC: 32132 AN: 43610

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 18248 AN: 23502

East Asian (EAS) AF: 0.311 AC: 11685 AN: 37628

South Asian (SAS) AF: 0.662 AC: 51022 AN: 77076

European-Finnish (FIN) AF: 0.826 AC: 43429 AN: 52608

Middle Eastern (MID) AF: 0.790 AC: 2675 AN: 3384

European-Non Finnish (NFE) AF: 0.851 AC: 635376 AN: 746628

Other (OTH) AF: 0.792 AC: 36980 AN: 46720

GnomAD4 genome AF: 0.774 AC: 117805 AN: 152134 Hom.: 46463 Cov.: 32 AF XY: 0.768 AC XY: 57095 AN XY: 74382

African (AFR) AF: 0.710 AC: 29443 AN: 41470

American (AMR) AF: 0.759 AC: 11606 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2673 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1908 AN: 5162

South Asian (SAS) AF: 0.649 AC: 3131 AN: 4822

European-Finnish (FIN) AF: 0.819 AC: 8682 AN: 10596

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.849 AC: 57747 AN: 68012

Other (OTH) AF: 0.775 AC: 1636 AN: 2110

Alfa AF: 0.765 Hom.: 2426

Bravo AF: 0.768

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.067
DANN	Benign	0.35
PhyloP100		-1.5
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: rs1965791; hg19: chr2-223096709; COSMIC: COSV60588973;