rs140383655

Variant names:

• chr16-29813121-G-A
• rs140383655
• NM_145239.3:c.67G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_145239.3(PRRT2):​c.67G>A​(p.Glu23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,926 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.0690
• Publications: 11 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008098692).
• BP6: Variant 16-29813121-G-A is Benign according to our data. Variant chr16-29813121-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130039.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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.67G>A	p.Glu23Lys	missense	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.67G>A	p.Glu23Lys	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.67G>A	p.Glu23Lys	missense	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.67G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152140 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00108 AC: 270 AN: 250954 AF XY: 0.000980

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00208 AC: 3035 AN: 1461668 Hom.: 6 Cov.: 33 AF XY: 0.00197 AC XY: 1429 AN XY: 727148

African (AFR) AF: 0.000448 AC: 15 AN: 33474

American (AMR) AF: 0.00154 AC: 69 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00252 AC: 2799 AN: 1111916

Other (OTH) AF: 0.00212 AC: 128 AN: 60386

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152258 Hom.: 1 Cov.: 31 AF XY: 0.000981 AC XY: 73 AN XY: 74444

African (AFR) AF: 0.000433 AC: 18 AN: 41542

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00124

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.00251

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	1	Episodic kinesigenic dyskinesia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	PRRT2-related disorder (1)
-	-	1	Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.069
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.059
Sift	Benign	0.15	T
Sift4G	Benign	0.32	T
Polyphen		0.0060	B
Vest4		0.069
MVP		0.58
MPC		0.29
ClinPred		0.0044	T
GERP RS		-0.30
Varity_R		0.088
gMVP		0.20
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140383655; hg19: chr16-29824442; COSMIC: COSV99569196;