rs944092875

Variant names:

• chr16-29813799-T-C
• rs944092875
• NM_145239.3:c.745T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_145239.3(PRRT2):​c.745T>C​(p.Ser249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0790
• Publications: 1 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=0.20756918).

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.745T>C	p.Ser249Pro	missense	Exon 2 of 4	NP_660282.2
	PRRT2	NM_001256442.2		c.745T>C	p.Ser249Pro	missense	Exon 2 of 3	NP_001243371.1
	PRRT2	NM_001438121.1		c.745T>C	p.Ser249Pro	missense	Exon 2 of 3	NP_001425050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.745T>C	p.Ser249Pro	missense	Exon 2 of 4	ENSP00000351608.7
	ENSG00000280893	ENST00000609618.2	TSL:5	n.745T>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2
	PRRT2	ENST00000567659.3	TSL:2	c.745T>C	p.Ser249Pro	missense	Exon 2 of 3	ENSP00000456226.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459196 Hom.: 0 Cov.: 43 AF XY: 0.00000689 AC XY: 5 AN XY: 725956

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110616

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Episodic kinesigenic dyskinesia (1)
-	1	-	not provided (1)
-	1	-	PRRT2-Associated Paroxysmal Movement Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.079
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.051	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.23		Loss of phosphorylation at S249 (P = 0.0221)
MVP		0.85
MPC		0.98
ClinPred		0.86	D
GERP RS		3.7
Varity_R		0.30
gMVP		0.59
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs944092875; hg19: chr16-29825120; COSMIC: COSV54885190; COSMIC: COSV54885190;