chr16-29813701-C-T

Variant names:

• chr16-29813701-C-T
• rs76335820
• NM_145239.3:c.647C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145239.3(PRRT2):​c.647C>T​(p.Pro216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,582,354 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P216R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0096 (86 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 2.28
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008844793).
• BP6: Variant 16-29813701-C-T is Benign according to our data. Variant chr16-29813701-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0096 (13729/1430298) while in subpopulation NFE AF = 0.0112 (12229/1095530). AF 95% confidence interval is 0.011. There are 86 homozygotes in GnomAdExome4. There are 6733 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 86 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.647C>T	p.Pro216Leu	missense	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.647C>T	p.Pro216Leu	missense	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.647C>T	p.Pro216Leu	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.647C>T	p.Pro216Leu	missense	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.647C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.647C>T	p.Pro216Leu	missense	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 964 AN: 151936 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00971

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00687 AC: 1492 AN: 217286 AF XY: 0.00722

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.0000576

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00598

GnomAD4 exome AF: 0.00960 AC: 13729 AN: 1430298 Hom.: 86 Cov.: 36 AF XY: 0.00949 AC XY: 6733 AN XY: 709430

African (AFR) AF: 0.00108 AC: 35 AN: 32310

American (AMR) AF: 0.00274 AC: 112 AN: 40930

Ashkenazi Jewish (ASJ) AF: 0.000708 AC: 17 AN: 24004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.00346 AC: 284 AN: 81992

European-Finnish (FIN) AF: 0.0128 AC: 664 AN: 51922

Middle Eastern (MID) AF: 0.00267 AC: 15 AN: 5612

European-Non Finnish (NFE) AF: 0.0112 AC: 12229 AN: 1095530

Other (OTH) AF: 0.00634 AC: 373 AN: 58824

GnomAD4 genome AF: 0.00634 AC: 964 AN: 152056 Hom.: 1 Cov.: 31 AF XY: 0.00604 AC XY: 449 AN XY: 74328

African (AFR) AF: 0.00166 AC: 69 AN: 41500

American (AMR) AF: 0.00412 AC: 63 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4812

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00971 AC: 660 AN: 67950

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00431 Hom.: 0

Bravo AF: 0.00538

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00254 AC: 11

ESP6500EA AF: 0.00728 AC: 62

ExAC AF: 0.00674 AC: 815

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	1	Episodic kinesigenic dyskinesia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Seizure (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	0.21
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.38	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.32
MVP		0.98
MPC		0.86
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.36
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs76335820; hg19: chr16-29825022; COSMIC: COSV108056221; COSMIC: COSV108056221;