16-29814628-T-G

Variant names:

• chr16-29814628-T-G
• rs144540943
• NM_145239.3:c.1013T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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. V338L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34065858).

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.1013T>G	p.Val338Gly	missense splice_region	Exon 4 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.1175T>G	p.Val392Gly	missense	Exon 3 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.1175T>G	p.Val392Gly	missense	Exon 3 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.1013T>G	p.Val338Gly	missense splice_region	Exon 4 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.1001+163T>G		intron	N/A	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.1175T>G	p.Val392Gly	missense	Exon 3 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445670 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719624

⚠️ 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: 32846

American (AMR) AF: 0.00 AC: 0 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 38488

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101582

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0041	T
Eigen	Benign	0.085
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.18	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.85	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.020	D
Sift4G	Benign	0.077	T
Polyphen		0.98	D
Vest4		0.41
MutPred		0.38		Loss of stability (P = 0.0067)
MVP		0.84
MPC		0.31
ClinPred		0.40	T
GERP RS		3.7
PromoterAI		-0.016	Neutral
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

Other links and lift over

dbSNP: rs144540943; hg19: chr16-29825949;