Genetic Variant SPDYE2:p.Val44Glu (chr7-102553386-T-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001396242.1(SPDYE2):c.131T>A(p.Val44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.017 ( 21 hom., cov: 0)

Exomes 𝑓: 0.0048 ( 19 hom. )

Failed GnomAD Quality Control

Consequence

SPDYE2
NM_001396242.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00400

Publications

1 publications found

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:

POLR2J3-UPK3BL2 (HGNC:58364):

POLR2J3-UPK3BL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00617674).

BP6

Variant 7-102553386-T-A is Benign according to our data. Variant chr7-102553386-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3168756.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00476 (112/23528) while in subpopulation AFR AF = 0.0236 (100/4236). AF 95% confidence interval is 0.0199. There are 19 homozygotes in GnomAdExome4. There are 48 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396242.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE2	NM_001396242.1	MANE Select	c.131T>A	p.Val44Glu	missense	Exon 2 of 9	NP_001383171.1	Q495Y8-1
SPDYE2	NM_001031618.3		c.131T>A	p.Val44Glu	missense	Exon 2 of 9	NP_001026789.2	Q495Y8-1
POLR2J3-UPK3BL2	NR_173351.1		n.465-11724A>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPDYE2	ENST00000691607.2	MANE Select	c.131T>A	p.Val44Glu	missense	Exon 2 of 9	ENSP00000509749.1	Q495Y8-1
ENSG00000270249	ENST00000514917.3	TSL:3	c.749-11724A>T		intron	N/A	ENSP00000423309.4	H0Y980
POLR2J3	ENST00000513506.6	TSL:5	c.383-11724A>T		intron	N/A	ENSP00000421085.1	E7EWC6

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

150

AN:

8896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00503

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:

0.00211

Gnomad OTH

AF:

0.0109

GnomAD2 exomes

AF:

0.0106

AC:

AN:

1790

AF XY:

0.00839

show subpopulations

Gnomad AFR exome

AF:

0.0213

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:

0.00476

AC:

112

AN:

23528

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

AN XY:

12282

show subpopulations

African (AFR)

AF:

0.0236

AC:

100

AN:

4236

American (AMR)

AF:

0.00190

AC:

AN:

1576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

220

East Asian (EAS)

AF:

0.00

AC:

AN:

3184

South Asian (SAS)

AF:

0.000877

AC:

AN:

3422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.000240

AC:

AN:

8320

Other (OTH)

AF:

0.00274

AC:

AN:

1458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0169

AC:

151

AN:

8918

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

AN XY:

4020

show subpopulations

African (AFR)

AF:

0.0220

AC:

145

AN:

6586

American (AMR)

AF:

0.00498

AC:

AN:

602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

336

South Asian (SAS)

AF:

0.00

AC:

AN:

118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00212

AC:

AN:

944

Other (OTH)

AF:

0.0109

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00371

Hom.:

ExAC

AF:

0.00435

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.086

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.49

M_CAP

Benign

0.0016

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

PhyloP100

-0.0040

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.069

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.23

MutPred

0.28

Gain of solvent accessibility (P = 0.0145)

ClinPred

0.21

Varity_R

0.37

gMVP

0.093

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over