4-25160758-G-T

Variant names:

• chr4-25160758-G-T
• rs73094683
• ENST00000512921.4:c.-21+5G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Publications: 7 publications found

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]

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

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 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Broad Center for Mendelian Genomics, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive cerebello-cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000512921.4. 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
	SEPSECS-DT	NR_037934.1		n.82+5G>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4K2B	ENST00000512921.4	TSL:2	c.-21+5G>T		splice_region intron	N/A	ENSP00000423373.1	G5E9Z4
	SEPSECS-AS1	ENST00000507794.2	TSL:2	n.82+5G>T		splice_region intron	N/A
	SEPSECS-AS1	ENST00000510415.1	TSL:2	n.113+5G>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14254 AN: 152144 Hom.: 769 Cov.: 32

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.: 0 AF XY: 0.0740 AC XY: 1860 AN XY: 25136

African (AFR) AF: 0.114 AC: 121 AN: 1060

American (AMR) AF: 0.0833 AC: 216 AN: 2594

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 90 AN: 1202

East Asian (EAS) AF: 0.00331 AC: 7 AN: 2114

South Asian (SAS) AF: 0.0741 AC: 562 AN: 7584

European-Finnish (FIN) AF: 0.0428 AC: 122 AN: 2848

Middle Eastern (MID) AF: 0.106 AC: 15 AN: 142

European-Non Finnish (NFE) AF: 0.0771 AC: 2099 AN: 27240

Other (OTH) AF: 0.0785 AC: 209 AN: 2662

GnomAD4 genome AF: 0.0937 AC: 14268 AN: 152262 Hom.: 768 Cov.: 32 AF XY: 0.0922 AC XY: 6867 AN XY: 74456

African (AFR) AF: 0.125 AC: 5208 AN: 41534

American (AMR) AF: 0.0959 AC: 1468 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.00636 AC: 33 AN: 5186

South Asian (SAS) AF: 0.0796 AC: 384 AN: 4822

European-Finnish (FIN) AF: 0.0429 AC: 456 AN: 10622

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0900 AC: 6117 AN: 68002

Other (OTH) AF: 0.0999 AC: 211 AN: 2112

Alfa AF: 0.0314 Hom.: 21

Bravo AF: 0.0981

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-0.22
PromoterAI		-0.055	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73094683; hg19: chr4-25162380;