Genetic Variant NM_012398.3:c.1997G>A (chr19-3633444-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012398.3(PIP5K1C):c.1997G>A(p.Ser666Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,497,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PIP5K1C
NM_012398.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

Publications

1 publications found

Variant links:

Genes affected

PIP5K1C (HGNC:8996): (phosphatidylinositol-4-phosphate 5-kinase type 1 gamma) This locus encodes a type I phosphatidylinositol 4-phosphate 5-kinase. The encoded protein catalyzes phosphorylation of phosphatidylinositol 4-phosphate, producing phosphatidylinositol 4,5-bisphosphate. This enzyme is found at synapses and has been found to play roles in endocytosis and cell migration. Mutations at this locus have been associated with lethal congenital contractural syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Sep 2010]

PIP5K1C Gene-Disease associations (from GenCC):

lethal congenital contracture syndrome 3
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

PIP5K1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.109078944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012398.3. 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
	PIP5K1C	NM_012398.3	MANE Select	c.1997G>A	p.Ser666Asn	missense	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-275G>A		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1997G>A	p.Ser666Asn	missense	Exon 17 of 18	ENSP00000335333.3	O60331-1
PIP5K1C	ENST00000876625.1		c.2114G>A	p.Ser705Asn	missense	Exon 18 of 19	ENSP00000546684.1
PIP5K1C	ENST00000967141.1		c.2099G>A	p.Ser700Asn	missense	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000491

AC:

AN:

162928

AF XY:

0.0000798

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000130

Gnomad OTH exome

AF:

0.000272

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1345660

Hom.:

Cov.:

AF XY:

0.0000532

AC XY:

AN XY:

658106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30084

American (AMR)

AF:

0.00

AC:

AN:

31064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19732

East Asian (EAS)

AF:

0.00

AC:

AN:

37552

South Asian (SAS)

AF:

0.000505

AC:

AN:

67312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46780

Middle Eastern (MID)

AF:

0.000193

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

1052792

Other (OTH)

AF:

0.0000181

AC:

AN:

55172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000525

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000336

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.055

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

6.5

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.65

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.13

Polyphen

0.42

Vest4

0.48

MutPred

0.10

Loss of phosphorylation at S666 (P = 0.0157)

MVP

0.44

MPC

0.46

ClinPred

0.20

GERP RS

3.4

Varity_R

0.37

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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