rs2855268

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-222202200-C-G
• chr2-222202200-C-T
• chr2-222202200-C-A

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.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:8
• Conservation: PhyloP100: -1.14
• Publications: 9 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: G2P, Orphanet, 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-222202200-C-G is Benign according to our data. Variant chr2-222202200-C-G is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.1174-10G>C		intron	N/A	NP_852123.1	P23760-7
	PAX3	NM_181459.4		c.1174-10G>C		intron	N/A	NP_852124.1	P23760-8
	PAX3	NM_001127366.3		c.1171-10G>C		intron	N/A	NP_001120838.1	P23760-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.1174-10G>C		intron	N/A	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.1171-10G>C		intron	N/A	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.1174-758G>C		intron	N/A	ENSP00000338767.5	P23760-5

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

GnomAD2 exomes AF: 0.108 AC: 20972 AN: 194398 AF XY: 0.106

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 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

African (AFR) AF: 0.0809 AC: 2620 AN: 32372

American (AMR) AF: 0.0977 AC: 3841 AN: 39308

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4901 AN: 25494

East Asian (EAS) AF: 0.000158 AC: 6 AN: 37940

South Asian (SAS) AF: 0.0372 AC: 3060 AN: 82178

European-Finnish (FIN) AF: 0.115 AC: 5918 AN: 51334

Middle Eastern (MID) AF: 0.182 AC: 975 AN: 5352

European-Non Finnish (NFE) AF: 0.144 AC: 155378 AN: 1081980

Other (OTH) AF: 0.133 AC: 7778 AN: 58634

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

African (AFR) AF: 0.0792 AC: 3289 AN: 41506

American (AMR) AF: 0.145 AC: 2208 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4820

European-Finnish (FIN) AF: 0.118 AC: 1254 AN: 10594

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9629 AN: 68000

Other (OTH) AF: 0.149 AC: 314 AN: 2110

Alfa AF: 0.0940 Hom.: 182

Bravo AF: 0.117

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Craniofacial-deafness-hand syndrome (1)
-	-	1	Waardenburg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2855268; hg19: chr2-223066919;