2-222297305-T-G

Variant names:

• chr2-222297305-T-G
• rs6754024
• NM_181458.4:c.86-92A>C

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.86-92A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 977,376 control chromosomes in the GnomAD database, including 359,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56006 hom., cov: 35)
  • Exomes 𝑓: 0.86 (303087 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.227
• Publications: 14 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=-0.9).
• BP6: Variant 2-222297305-T-G is Benign according to our data. Variant chr2-222297305-T-G is described in ClinVar as Benign. ClinVar VariationId is 1288499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.86-92A>C		intron	N/A	NP_852123.1
	PAX3	NM_181459.4		c.86-92A>C		intron	N/A	NP_852124.1
	PAX3	NM_001127366.3		c.86-92A>C		intron	N/A	NP_001120838.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.86-92A>C		intron	N/A	ENSP00000375922.3
	PAX3	ENST00000409551.7	TSL:1	c.86-92A>C		intron	N/A	ENSP00000386750.3
	PAX3	ENST00000336840.11	TSL:1	c.86-92A>C		intron	N/A	ENSP00000338767.5

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130242 AN: 152176 Hom.: 55955 Cov.: 35

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.888

GnomAD4 exome AF: 0.855 AC: 705550 AN: 825082 Hom.: 303087 AF XY: 0.860 AC XY: 368503 AN XY: 428540

African (AFR) AF: 0.830 AC: 17023 AN: 20514

American (AMR) AF: 0.930 AC: 32546 AN: 35006

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 19933 AN: 21570

East Asian (EAS) AF: 1.00 AC: 33108 AN: 33114

South Asian (SAS) AF: 0.951 AC: 63719 AN: 66994

European-Finnish (FIN) AF: 0.831 AC: 39171 AN: 47114

Middle Eastern (MID) AF: 0.941 AC: 3081 AN: 3274

European-Non Finnish (NFE) AF: 0.829 AC: 462933 AN: 558492

Other (OTH) AF: 0.873 AC: 34036 AN: 39004

GnomAD4 genome AF: 0.856 AC: 130350 AN: 152294 Hom.: 56006 Cov.: 35 AF XY: 0.858 AC XY: 63926 AN XY: 74470

African (AFR) AF: 0.837 AC: 34801 AN: 41562

American (AMR) AF: 0.912 AC: 13953 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3209 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5190

South Asian (SAS) AF: 0.953 AC: 4603 AN: 4832

European-Finnish (FIN) AF: 0.829 AC: 8792 AN: 10600

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57083 AN: 68016

Other (OTH) AF: 0.889 AC: 1879 AN: 2114

Alfa AF: 0.856 Hom.: 105685

Bravo AF: 0.860

Asia WGS AF: 0.969 AC: 3370 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	4.2
DANN	Benign	0.46
PhyloP100		-0.23
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: rs6754024; hg19: chr2-223162024;