1-96785224-G-A

Position:

• chr1-96785224-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_021190.4(PTBP2):​c.874G>A​(p.Ala292Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,444,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PTBP2 NM_021190.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

Genes affected

PTBP2 (HGNC:17662): (polypyrimidine tract binding protein 2) The protein encoded by this gene binds to intronic polypyrimidine clusters in pre-mRNA molecules and is implicated in controlling the assembly of other splicing-regulatory proteins. This protein is very similar to the polypyrimidine tract binding protein (PTB) but most of its isoforms are expressed primarily in the brain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21831498).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTBP2	NM_021190.4	c.874G>A	p.Ala292Thr	missense_variant	8/14	ENST00000674951.1	NP_067013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTBP2	ENST00000674951.1	c.874G>A	p.Ala292Thr	missense_variant	8/14		NM_021190.4	ENSP00000502818	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444898 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 718700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.874G>A (p.A292T) alteration is located in exon 8 (coding exon 8) of the PTBP2 gene. This alteration results from a G to A substitution at nucleotide position 874, causing the alanine (A) at amino acid position 292 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	.;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.11	.;T;T;T
Sift4G	Uncertain	0.060	T;T;T;T
Polyphen		0.016	B;D;B;B
Vest4		0.31
MVP		0.54
MPC		1.2
ClinPred		0.63	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.28
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1321699119; hg19: chr1-97250780;