16-29813728-A-C

Variant names:

• chr16-29813728-A-C
• rs1057518890
• NM_145239.3:c.674A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_145239.3(PRRT2):​c.674A>C​(p.Glu225Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,345,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E225G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: PRRT2 NM_145239.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15430713).
• BP6: Variant 16-29813728-A-C is Benign according to our data. Variant chr16-29813728-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 857864.

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.674A>C	p.Glu225Ala	missense	Exon 2 of 4	NP_660282.2	Q7Z6L0-1
	PRRT2	NM_001256442.2		c.674A>C	p.Glu225Ala	missense	Exon 2 of 3	NP_001243371.1	Q7Z6L0-2
	PRRT2	NM_001438121.1		c.674A>C	p.Glu225Ala	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.674A>C	p.Glu225Ala	missense	Exon 2 of 4	ENSP00000351608.7	Q7Z6L0-1
	ENSG00000280893	ENST00000609618.2	TSL:5	n.674A>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000476774.2	A0A0G2JLL6
	PRRT2	ENST00000567659.3	TSL:2	c.674A>C	p.Glu225Ala	missense	Exon 2 of 3	ENSP00000456226.1	Q7Z6L0-2

Frequencies

GnomAD3 genomes AF: 0.0000281 AC: 4 AN: 142316 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000910 AC: 2 AN: 219678 AF XY: 0.00

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1202844 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 594096

African (AFR) AF: 0.0000781 AC: 2 AN: 25608

American (AMR) AF: 0.00 AC: 0 AN: 34056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15334

East Asian (EAS) AF: 0.00 AC: 0 AN: 18050

South Asian (SAS) AF: 0.00 AC: 0 AN: 79344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 949380

Other (OTH) AF: 0.00 AC: 0 AN: 43852

GnomAD4 genome AF: 0.0000281 AC: 4 AN: 142316 Hom.: 0 Cov.: 31 AF XY: 0.0000435 AC XY: 3 AN XY: 68996

African (AFR) AF: 0.000101 AC: 4 AN: 39468

American (AMR) AF: 0.00 AC: 0 AN: 14478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 4104

South Asian (SAS) AF: 0.00 AC: 0 AN: 3902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64902

Other (OTH) AF: 0.00 AC: 0 AN: 2000

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Episodic kinesigenic dyskinesia (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.27		Loss of solvent accessibility (P = 0.0053)
MVP		0.94
MPC		0.90
ClinPred		0.37	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057518890; hg19: chr16-29825049;