19-18161380-A-C

Variant names:

• chr19-18161380-A-C
• rs2241088
• NM_005027.4:c.700A>C

Variant summary

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

The NM_005027.4(PIK3R2):​c.700A>C​(p.Ser234Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,241,468 control chromosomes in the GnomAD database, including 536,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S234N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.93 (65204 hom., cov: 32)
  • Exomes 𝑓: 0.93 (470908 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29
• Publications: 30 publications found

Genes affected

PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

PIK3R2 Gene-Disease associations (from GenCC):

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000268173 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7992236E-7).
• BP6: Variant 19-18161380-A-C is Benign according to our data. Variant chr19-18161380-A-C is described in ClinVar as Benign. ClinVar VariationId is 497079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	NM_005027.4	MANE Select	c.700A>C	p.Ser234Arg	missense	Exon 6 of 16	NP_005018.2
	PIK3R2	NR_073517.2		n.1255A>C		non_coding_transcript_exon	Exon 6 of 16
	PIK3R2	NR_162071.1		n.1153+195A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.700A>C	p.Ser234Arg	missense	Exon 6 of 16	ENSP00000222254.6
	ENSG00000268173	ENST00000593731.1	TSL:2	n.700A>C		non_coding_transcript_exon	Exon 6 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.598+195A>C		intron	N/A	ENSP00000477864.2

Frequencies

GnomAD3 genomes AF: 0.932 AC: 139727 AN: 149952 Hom.: 65157 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.938

GnomAD2 exomes AF: 0.885 AC: 8559 AN: 9668 AF XY: 0.885

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.833

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.915

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.929 AC: 1013468 AN: 1091408 Hom.: 470908 Cov.: 43 AF XY: 0.928 AC XY: 482883 AN XY: 520302

African (AFR) AF: 0.971 AC: 21400 AN: 22028

American (AMR) AF: 0.887 AC: 8020 AN: 9046

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 13000 AN: 14072

East Asian (EAS) AF: 0.928 AC: 22406 AN: 24138

South Asian (SAS) AF: 0.867 AC: 23332 AN: 26922

European-Finnish (FIN) AF: 0.884 AC: 19908 AN: 22516

Middle Eastern (MID) AF: 0.900 AC: 2615 AN: 2906

European-Non Finnish (NFE) AF: 0.931 AC: 862706 AN: 926536

Other (OTH) AF: 0.927 AC: 40081 AN: 43244

GnomAD4 genome AF: 0.932 AC: 139827 AN: 150060 Hom.: 65204 Cov.: 32 AF XY: 0.926 AC XY: 67862 AN XY: 73274

African (AFR) AF: 0.971 AC: 40117 AN: 41310

American (AMR) AF: 0.892 AC: 13451 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3207 AN: 3444

East Asian (EAS) AF: 0.910 AC: 4669 AN: 5128

South Asian (SAS) AF: 0.878 AC: 4240 AN: 4828

European-Finnish (FIN) AF: 0.875 AC: 8551 AN: 9776

Middle Eastern (MID) AF: 0.938 AC: 274 AN: 292

European-Non Finnish (NFE) AF: 0.930 AC: 62466 AN: 67198

Other (OTH) AF: 0.936 AC: 1956 AN: 2090

Alfa AF: 0.935 Hom.: 8248

Bravo AF: 0.937

TwinsUK AF: 0.940 AC: 3484

ALSPAC AF: 0.943 AC: 3635

ExAC AF: 0.826 AC: 6407

Asia WGS AF: 0.886 AC: 2787 AN: 3146

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.066	T
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.82	N
REVEL	Benign	0.0090
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.32		Gain of MoRF binding (P = 0.0219)
MPC		0.31
ClinPred		0.0014	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.29
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2241088; hg19: chr19-18272190; COSMIC: COSV55848697; COSMIC: COSV55848697;