7-102554373-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001396242.1(SPDYE2):c.175C>A(p.Pro59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPDYE2
NM_001396242.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.653

Variant links:

Genes affected

SPDYE2 (HGNC:33841): (speedy/RINGO cell cycle regulator family member E2) Predicted to enable protein kinase binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SPDYE2 links:

ENSG00000270249 (HGNC:):

ENSG00000270249 links:

POLR2J3 (HGNC:33853): (RNA polymerase II subunit J3) This gene is a member of the RNA polymerase II subunit 11 gene family, which includes three genes in a cluster on chromosome 7q22.1 and a pseudogene on chromosome 7p13. The founding member of this family, DNA directed RNA polymerase II polypeptide J, has been shown to encode a subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This locus produces multiple, alternatively spliced transcripts that potentially express isoforms with distinct C-termini compared to DNA directed RNA polymerase II polypeptide J. Most or all variants are spliced to include additional non-coding exons at the 3' end which makes them candidates for nonsense-mediated decay (NMD). Consequently, it is not known if this locus expresses a protein or proteins in vivo. [provided by RefSeq, Jul 2008]

POLR2J3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09321463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE2	NM_001396242.1 link	c.175C>A	p.Pro59Thr	missense_variant	Exon 3 of 9	ENST00000691607.2	NP_001383171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPDYE2	ENST00000691607.2 link	c.175C>A	p.Pro59Thr	missense_variant	Exon 3 of 9		NM_001396242.1	ENSP00000509749.1	Q495Y8-1
ENSG00000270249	ENST00000514917.3 link	c.748+12209G>T		intron_variant	Intron 6 of 6	3		ENSP00000423309.4	H0Y980
POLR2J3	ENST00000513506.6 link	c.382+12209G>T		intron_variant	Intron 4 of 6	5		ENSP00000421085.1	E7EWC6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150740

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

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

GnomAD3 exomes

AF:

0.0000816

AC:

AN:

49046

Hom.:

AF XY:

0.0000406

AC XY:

AN XY:

24658

show subpopulations

Gnomad AFR exome

AF:

0.000836

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000244

AC:

AN:

1435346

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

713972

show subpopulations

Gnomad4 AFR exome

AF:

0.000572

Gnomad4 AMR exome

AF:

0.000138

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:

0.00

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000146

AC:

AN:

150858

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

73642

show subpopulations

Gnomad4 AFR

AF:

0.000507

Gnomad4 AMR

AF:

0.0000664

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175C>A (p.P59T) alteration is located in exon 3 (coding exon 2) of the SPDYE2 gene. This alteration results from a C to A substitution at nucleotide position 175, causing the proline (P) at amino acid position 59 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.65

.;T

M_CAP

Benign

0.00089

MetaRNN

Benign

0.093

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

D;.

REVEL

Benign

0.075

Sift

Uncertain

0.011

D;.

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;D

Vest4

0.089

MutPred

0.15

Gain of phosphorylation at P59 (P = 0.0165);Gain of phosphorylation at P59 (P = 0.0165);

MVP

0.061

ClinPred

0.15

Varity_R

0.11

gMVP

0.059

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over