16-29813694-G-A

Variant names:

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

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.640G>A​(p.Ala214Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,922 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. 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. A214P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749
• 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=0.22699037).

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>A	p.Ala214Thr	missense	Exon 2 of 4	NP_660282.2
	PRRT2	NM_001256442.2		c.640G>A	p.Ala214Thr	missense	Exon 2 of 3	NP_001243371.1
	PRRT2	NM_001438121.1		c.640G>A	p.Ala214Thr	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>A	p.Ala214Thr	missense	Exon 2 of 4	ENSP00000351608.7
	ENSG00000280893	ENST00000609618.2	TSL:5	n.640G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2
	PRRT2	ENST00000567659.3	TSL:2	c.640G>A	p.Ala214Thr	missense	Exon 2 of 3	ENSP00000456226.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355922 Hom.: 0 Cov.: 36 AF XY: 0.00000149 AC XY: 1 AN XY: 672634

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

African (AFR) AF: 0.00 AC: 0 AN: 30504

American (AMR) AF: 0.00 AC: 0 AN: 38056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22842

East Asian (EAS) AF: 0.00 AC: 0 AN: 37316

South Asian (SAS) AF: 0.00 AC: 0 AN: 76988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038632

Other (OTH) AF: 0.0000179 AC: 1 AN: 56014

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.75
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.13
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.15		Gain of helix (P = 6e-04)
MVP		0.86
MPC		0.86
ClinPred		0.80	D
GERP RS		3.9
Varity_R		0.081
gMVP		0.15
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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;