NM_145239.3:c.879+6C>A

Variant names:

• chr16-29813939-C-A
• rs201887920
• NM_145239.3:c.879+6C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_145239.3(PRRT2):​c.879+6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,570,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PRRT2 NM_145239.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.346
• Publications: 2 publications found

Genes affected

PRRT2 (HGNC:30500): (proline rich transmembrane protein 2) This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages. Mutations in this gene are associated with episodic kinesigenic dyskinesia-1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ENSG00000280893 (HGNC:):

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.268013).
• BP6: Variant 16-29813939-C-A is Benign according to our data. Variant chr16-29813939-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468621.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145239.3. 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
	PRRT2	NM_145239.3	MANE Select	c.879+6C>A		splice_region intron	N/A	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256443.2		c.885C>A	p.Ser295Arg	missense	Exon 2 of 2	NP_001243372.1	Q7Z6L0-3
	PRRT2	NM_001438122.1		c.885C>A	p.Ser295Arg	missense	Exon 2 of 2	NP_001425051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.879+6C>A		splice_region intron	N/A	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.879+6C>A		splice_region intron	N/A	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000300797.7	TSL:2	c.885C>A	p.Ser295Arg	missense	Exon 2 of 2	ENSP00000300797.6	Q7Z6L0-3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000233 AC: 5 AN: 214276 AF XY: 0.0000174

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000134 AC: 19 AN: 1418130 Hom.: 0 Cov.: 35 AF XY: 0.00000998 AC XY: 7 AN XY: 701338

African (AFR) AF: 0.000591 AC: 19 AN: 32142

American (AMR) AF: 0.00 AC: 0 AN: 39276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23276

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00 AC: 0 AN: 79406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089086

Other (OTH) AF: 0.00 AC: 0 AN: 58370

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74414

African (AFR) AF: 0.000385 AC: 16 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Episodic kinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.24	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		0.35
PROVEAN	Benign	2.7	N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.29		Loss of glycosylation at S295 (P = 0.0013)
MVP		0.94
ClinPred		0.090	T
GERP RS		2.2
PromoterAI		-0.030	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201887920; hg19: chr16-29825260;