Genetic Variant NM_145239.3:c.1013T>G (chr16-29814628-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145239.3(PRRT2):c.1013T>G(p.Val338Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V338A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRRT2
NM_145239.3 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

0 publications found

Variant links:

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]

PRRT2 links:

ENSG00000280893 (HGNC:):

ENSG00000280893 links:

MVP-DT (HGNC:56029): (MVP divergent transcript)

MVP-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34065858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3 link	c.1013T>G	p.Val338Gly	missense_variant, splice_region_variant	Exon 4 of 4	ENST00000358758.12	NP_660282.2	Q7Z6L0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12 link	c.1013T>G	p.Val338Gly	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_145239.3	ENSP00000351608.7		Q7Z6L0-1
ENSG00000280893	ENST00000609618.2 link	n.1001+163T>G		intron_variant	Intron 3 of 5	5		ENSP00000476774.2		A0A0G2JLL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719624

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32846

American (AMR)

AF:

0.00

AC:

AN:

44122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25254

East Asian (EAS)

AF:

0.00

AC:

AN:

38488

South Asian (SAS)

AF:

0.00

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101582

Other (OTH)

AF:

0.00

AC:

AN:

59248

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0041

T;.;T;T;T

Eigen

Benign

0.085

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.18

.;T;.;.;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.90

L;.;L;L;L

PhyloP100

1.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.85

N;N;.;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.020

D;D;.;.;.

Sift4G

Benign

0.077

T;D;.;T;.

Polyphen

0.98

D;D;D;D;D

Vest4

0.41

MutPred

0.38

Loss of stability (P = 0.0067);.;Loss of stability (P = 0.0067);Loss of stability (P = 0.0067);Loss of stability (P = 0.0067);

MVP

0.84

MPC

0.31

ClinPred

0.40

GERP RS

3.7

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.11

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over