NM_145239.3:c.224C>G

Variant names:

• chr16-29813278-C-G
• rs147004110
• NM_145239.3:c.224C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145239.3(PRRT2):​c.224C>G​(p.Pro75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P75L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16627765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.224C>G	p.Pro75Arg	missense_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.224C>G	p.Pro75Arg	missense_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.224C>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461652 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRRT2-related disorder Uncertain:1

Apr 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRRT2 c.224C>G variant is predicted to result in the amino acid substitution p.Pro75Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate missense variant (p.Pro75Leu) has been reported to be maternally inherited in a patient with a personal and family history of seizures (Luo et al. 2021. PubMed ID: 34041212). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	.;.;T;.;T;.;.;.;.;T;.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.61	T;T;.;.;T;T;T;T;T;.;T;.;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	.;.;L;L;.;L;.;.;L;L;.;L;L;.
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.2	.;D;N;.;.;N;.;.;N;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.043	.;D;D;.;.;D;.;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;D;.;.;D;.;.;D;.;.
Polyphen		0.94, 0.98, 0.96	.;.;P;D;.;D;.;.;D;P;.;P;P;.
Vest4		0.39, 0.40, 0.39, 0.39
MutPred		0.17		Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);Loss of glycosylation at T72 (P = 0.0673);
MVP		0.80
MPC		0.88
ClinPred		0.84	D
GERP RS		2.0
Varity_R		0.055
gMVP		0.076

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

dbSNP: rs147004110; hg19: chr16-29824599;