rs779020826

Positions:

• chr16-29813689-A-C
• chr16-29813689-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_145239.3(PRRT2):​c.635A>C​(p.Asn212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 141,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1440725).
• BS2: High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.635A>C	p.Asn212Thr	missense_variant	2/4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.635A>C	p.Asn212Thr	missense_variant	2/4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.635A>C		non_coding_transcript_exon_variant	2/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes AF: 0.0000637 AC: 9 AN: 141230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000247

Gnomad SAS AF: 0.000261

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000780

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000144 AC: 13 AN: 900992 Hom.: 0 Cov.: 32 AF XY: 0.0000109 AC XY: 5 AN XY: 457472

Gnomad4 AFR exome AF: 0.0000501

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000293

GnomAD4 genome AF: 0.0000707 AC: 10 AN: 141376 Hom.: 0 Cov.: 31 AF XY: 0.0000437 AC XY: 3 AN XY: 68698

Gnomad4 AFR AF: 0.0000506

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000247

Gnomad4 SAS AF: 0.000260

Gnomad4 FIN AF: 0.000112

Gnomad4 NFE AF: 0.0000780

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.635A>C (p.N212T) alteration is located in exon 2 (coding exon 1) of the PRRT2 gene. This alteration results from a A to C substitution at nucleotide position 635, causing the asparagine (N) at amino acid position 212 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T;.;.;.;.;T;.;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	.;.;T;T;T;.;T;.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	L;L;L;.;L;L;.;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.64	N;.;N;.;N;.;.;.;.
REVEL	Benign	0.087
Sift	Uncertain	0.0020	D;.;D;.;D;.;.;.;.
Sift4G	Benign	0.13	T;.;T;.;T;.;.;T;.
Polyphen		0.26	B;P;B;.;P;B;.;B;B
Vest4		0.40
MutPred		0.16		Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);Gain of phosphorylation at N212 (P = 0.0045);
MVP		0.77
MPC		0.88
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs779020826; hg19: chr16-29825010;