Genetic Variant ENST00000512921.4:c.-21+5G>T (chr4-25160758-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000512921.4(PI4K2B):c.-21+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 199,708 control chromosomes in the GnomAD database, including 945 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 768 hom., cov: 32)

Exomes 𝑓: 0.073 ( 177 hom. )

Consequence

PI4K2B
ENST00000512921.4 splice_region, intron

Scores

Splicing: ADA: 0.00006381

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.223

Variant links:

Genes affected

PI4K2B (HGNC:18215): (phosphatidylinositol 4-kinase type 2 beta) This gene encodes a member of the type II PI4 kinase protein family. The encoded protein is primarily cytosolic and contributes to overall PI4-kinase activity along with other protein family members. This protein is involved in early T cell activation. [provided by RefSeq, Dec 2016]

PI4K2B links:

SEPSECS-AS1 (HGNC:27737): (SEPSECS antisense RNA 1 (head to head))

SEPSECS-AS1 links:

SEPSECS (HGNC:30605): (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase) The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

SEPSECS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 4-25160758-G-T is Benign according to our data. Variant chr4-25160758-G-T is described in ClinVar as [Benign]. Clinvar id is 1259706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS-AS1	NR_037934.1 link	n.82+5G>T		splice_region_variant, intron_variant	Intron 1 of 1
SEPSECS	XM_047415762.1 link	c.-280C>A		upstream_gene_variant			XP_047271718.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
PI4K2B	ENST00000512921.4 link	c.-21+5G>T	splice_region_variant, intron_variant	Intron 1 of 9	2	ENSP00000423373.1	G5E9Z4
SEPSECS-AS1	ENST00000507794.2 link	n.82+5G>T	splice_region_variant, intron_variant	Intron 1 of 1	2
SEPSECS-AS1	ENST00000510415.1 link	n.113+5G>T	splice_region_variant, intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0937

AC:

14254

AN:

152144

Hom.:

769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.0919

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.0792

Gnomad FIN

AF:

0.0429

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.0900

Gnomad OTH

AF:

0.101

GnomAD4 exome

AF:

0.0725

AC:

3441

AN:

47446

Hom.:

177

Cov.:

AF XY:

0.0740

AC XY:

1860

AN XY:

25136

show subpopulations

Gnomad4 AFR exome

AF:

0.114

Gnomad4 AMR exome

AF:

0.0833

Gnomad4 ASJ exome

AF:

0.0749

Gnomad4 EAS exome

AF:

0.00331

Gnomad4 SAS exome

AF:

0.0741

Gnomad4 FIN exome

AF:

0.0428

Gnomad4 NFE exome

AF:

0.0771

Gnomad4 OTH exome

AF:

0.0785

GnomAD4 genome

AF:

0.0937

AC:

14268

AN:

152262

Hom.:

768

Cov.:

AF XY:

0.0922

AC XY:

6867

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.0959

Gnomad4 ASJ

AF:

0.0919

Gnomad4 EAS

AF:

0.00636

Gnomad4 SAS

AF:

0.0796

Gnomad4 FIN

AF:

0.0429

Gnomad4 NFE

AF:

0.0900

Gnomad4 OTH

AF:

0.0999

Alfa

AF:

0.0274

Hom.:

Bravo

AF:

0.0981

Asia WGS

AF:

0.0470

AC:

164

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.8

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.18

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