2-222298562-C-G

Variant names:

• chr2-222298562-C-G
• NM_181458.4:c.54G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_181458.4(PAX3):​c.54G>C​(p.Gln18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.541
• Publications: 0 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]

CCDC140 (HGNC:26514): (CCDC140 long non-coding RNA) This gene encodes a protein that appears to be restricted to select higher primate species. This protein contains a C-terminal coiled-coil domain, which is a versatile structural motif consisting of multiple amphipathic alpha-helices that twist around each other to form a supercoil. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 1.618 (below the threshold of 3.09). Trascript score misZ: 1.7934 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome, craniofacial-deafness-hand syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37467277).

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.54G>C	p.Gln18His	missense	Exon 1 of 9	NP_852123.1	P23760-7
	PAX3	NM_181459.4		c.54G>C	p.Gln18His	missense	Exon 1 of 10	NP_852124.1	P23760-8
	PAX3	NM_001127366.3		c.54G>C	p.Gln18His	missense	Exon 1 of 9	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.54G>C	p.Gln18His	missense	Exon 1 of 9	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.54G>C	p.Gln18His	missense	Exon 1 of 9	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.54G>C	p.Gln18His	missense	Exon 1 of 9	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.97	L
PhyloP100		0.54
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.83	P
Vest4		0.25
MutPred		0.15		Gain of catalytic residue at N19 (P = 0.0553)
MVP		0.96
MPC		2.1
ClinPred		0.93	D
GERP RS		1.8
PromoterAI		-0.0083	Neutral
Varity_R		0.42
gMVP		0.93
Mutation Taster		=54/46	polymorphism

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

hg19: chr2-223163281;