2-222202200-C-G

Variant names:

• chr2-222202200-C-G
• rs2855268
• NM_181458.4:c.1174-10G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181458.4(PAX3):​c.1174-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,566,748 control chromosomes in the GnomAD database, including 14,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1207 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13028 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Scores: Splicing: ADA: 0.0001188
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-222202200-C-G is Benign according to our data. Variant chr2-222202200-C-G is described in ClinVar as [Benign]. Clinvar id is 226998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.1174-10G>C		intron_variant	Intron 7 of 8	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.1174-10G>C		intron_variant	Intron 7 of 8	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17619 AN: 152038 Hom.: 1208 Cov.: 31

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.108 AC: 20972 AN: 194398 Hom.: 1403 AF XY: 0.106 AC XY: 10948 AN XY: 103678

Gnomad AFR exome AF: 0.0738

Gnomad AMR exome AF: 0.0928

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.0379

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.130 AC: 184477 AN: 1414592 Hom.: 13028 Cov.: 29 AF XY: 0.128 AC XY: 89666 AN XY: 701240

Gnomad4 AFR exome AF: 0.0809

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.000158

Gnomad4 SAS exome AF: 0.0372

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.116 AC: 17609 AN: 152156 Hom.: 1207 Cov.: 31 AF XY: 0.114 AC XY: 8505 AN XY: 74372

Gnomad4 AFR AF: 0.0792

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.149

Alfa AF: 0.0940 Hom.: 182

Bravo AF: 0.117

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1174-10G>C in intron 7C of PAX3: This variant is not expected to have clinical s ignificance because it has been identified in 14.6% (1259/8598) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2855268). -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Craniofacial-deafness-hand syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Waardenburg syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs2855268; hg19: chr2-223066919;