16-29813694-G-C

Variant names:

• chr16-29813694-G-C
• rs745594874
• NM_145239.3:c.640G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_145239.3(PRRT2):​c.640G>C​(p.Ala214Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,355,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.749
• Publications: 14 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008581936).
• BP6: Variant 16-29813694-G-C is Benign according to our data. Variant chr16-29813694-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206687.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	NM_145239.3	MANE Select	c.640G>C	p.Ala214Pro	missense	Exon 2 of 4	NP_660282.2
	PRRT2	NM_001256442.2		c.640G>C	p.Ala214Pro	missense	Exon 2 of 3	NP_001243371.1
	PRRT2	NM_001438121.1		c.640G>C	p.Ala214Pro	missense	Exon 2 of 3	NP_001425050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRT2	ENST00000358758.12	TSL:1 MANE Select	c.640G>C	p.Ala214Pro	missense	Exon 2 of 4	ENSP00000351608.7
	ENSG00000280893	ENST00000609618.2	TSL:5	n.640G>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2
	PRRT2	ENST00000567659.3	TSL:2	c.640G>C	p.Ala214Pro	missense	Exon 2 of 3	ENSP00000456226.1

Frequencies

GnomAD3 genomes AF: 0.000916 AC: 137 AN: 149504 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.00276

Gnomad FIN AF: 0.0000969

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000581

Gnomad OTH AF: 0.000971

GnomAD2 exomes AF: 0.00152 AC: 206 AN: 135540 AF XY: 0.00165

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000680

Gnomad EAS exome AF: 0.00527

Gnomad FIN exome AF: 0.0000660

Gnomad NFE exome AF: 0.000910

Gnomad OTH exome AF: 0.000623

GnomAD4 exome AF: 0.000802 AC: 1087 AN: 1355752 Hom.: 1 Cov.: 36 AF XY: 0.000836 AC XY: 562 AN XY: 672552

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000787 AC: 24 AN: 30494

American (AMR) AF: 0.000473 AC: 18 AN: 38054

Ashkenazi Jewish (ASJ) AF: 0.000438 AC: 10 AN: 22842

East Asian (EAS) AF: 0.00378 AC: 141 AN: 37312

South Asian (SAS) AF: 0.00323 AC: 249 AN: 76978

European-Finnish (FIN) AF: 0.0000798 AC: 4 AN: 50146

Middle Eastern (MID) AF: 0.000369 AC: 2 AN: 5424

European-Non Finnish (NFE) AF: 0.000559 AC: 580 AN: 1038490

Other (OTH) AF: 0.00105 AC: 59 AN: 56012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000909 AC: 136 AN: 149604 Hom.: 2 Cov.: 31 AF XY: 0.000876 AC XY: 64 AN XY: 73022

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00155 AC: 63 AN: 40650

American (AMR) AF: 0.000266 AC: 4 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3436

East Asian (EAS) AF: 0.00235 AC: 12 AN: 5104

South Asian (SAS) AF: 0.00255 AC: 12 AN: 4710

European-Finnish (FIN) AF: 0.0000969 AC: 1 AN: 10318

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.000582 AC: 39 AN: 67064

Other (OTH) AF: 0.000962 AC: 2 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000472 Hom.: 0

ExAC AF: 0.00102 AC: 123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRRT2: BP4, BS1, BS2

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 14, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23496026, 27123484, 22101681, 26598493, 24594579, 27907910, 31124310)

not specified Benign:1

Mar 19, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Episodic kinesigenic dyskinesia Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Apr 19, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

PRRT2-related disorder Benign:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0052	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.75
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.21
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.58
MVP		0.87
MPC		1.0
ClinPred		0.023	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.21
Mutation Taster		=84/16	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

dbSNP: rs745594874; hg19: chr16-29825015; COSMIC: COSV54881935; COSMIC: COSV54881935;