Genetic Variant NM_012398.3:c.1966G>T (chr19-3633475-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012398.3(PIP5K1C):c.1966G>T(p.Ala656Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A656P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIP5K1C
NM_012398.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.473

Publications

0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

PIP5K1C links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05075714).

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.1966G>T	p.Ala656Ser	missense	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-306G>T		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.1966G>T	p.Ala656Ser	missense	Exon 17 of 18	ENSP00000335333.3	O60331-1
PIP5K1C	ENST00000876625.1		c.2083G>T	p.Ala695Ser	missense	Exon 18 of 19	ENSP00000546684.1
PIP5K1C	ENST00000967141.1		c.2068G>T	p.Ala690Ser	missense	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1359370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

666972

African (AFR)

AF:

0.00

AC:

AN:

30272

American (AMR)

AF:

0.00

AC:

AN:

31718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20438

East Asian (EAS)

AF:

0.00

AC:

AN:

37806

South Asian (SAS)

AF:

0.00

AC:

AN:

69750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059776

Other (OTH)

AF:

0.00

AC:

AN:

55670

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.055

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.53

M_CAP

Benign

0.045

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.11

PhyloP100

-0.47

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.30

REVEL

Benign

0.041

Sift

Benign

0.60

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.28

MutPred

0.11

Gain of glycosylation at A656 (P = 0.0053)

MVP

0.36

MPC

0.30

ClinPred

0.053

GERP RS

-6.2

Varity_R

0.036

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over