chr19-3633466-G-A

Variant names:

• chr19-3633466-G-A
• rs34633286
• NM_012398.3:c.1975C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012398.3(PIP5K1C):​c.1975C>T​(p.Pro659Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00604 in 1,508,592 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (35 hom.)
• Consequence: PIP5K1C NM_012398.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.11
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006764978).
• BP6: Variant 19-3633466-G-A is Benign according to our data. Variant chr19-3633466-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 708469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1975C>T	p.Pro659Ser	missense	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-297C>T		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1975C>T	p.Pro659Ser	missense	Exon 17 of 18	ENSP00000335333.3	O60331-1
	PIP5K1C	ENST00000876625.1		c.2092C>T	p.Pro698Ser	missense	Exon 18 of 19	ENSP00000546684.1
	PIP5K1C	ENST00000967141.1		c.2077C>T	p.Pro693Ser	missense	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00676

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00302 AC: 523 AN: 173244 AF XY: 0.00308

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00631 AC: 8557 AN: 1356256 Hom.: 35 Cov.: 31 AF XY: 0.00605 AC XY: 4023 AN XY: 664562

African (AFR) AF: 0.000928 AC: 28 AN: 30162

American (AMR) AF: 0.000482 AC: 15 AN: 31130

Ashkenazi Jewish (ASJ) AF: 0.0000496 AC: 1 AN: 20142

East Asian (EAS) AF: 0.000185 AC: 7 AN: 37924

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 69118

European-Finnish (FIN) AF: 0.00243 AC: 118 AN: 48574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5236

European-Non Finnish (NFE) AF: 0.00776 AC: 8209 AN: 1058388

Other (OTH) AF: 0.00320 AC: 178 AN: 55582

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74500

African (AFR) AF: 0.00147 AC: 61 AN: 41578

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00676 AC: 460 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00506 Hom.: 5

Bravo AF: 0.00346

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00293 AC: 353

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.031
Sift	Benign	0.12	T
Sift4G	Benign	0.27	T
Polyphen		0.010	B
Vest4		0.33
MVP		0.14
MPC		0.33
ClinPred		0.0080	T
GERP RS		2.8
Varity_R		0.058
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs34633286; hg19: chr19-3633464; COSMIC: COSV100096397; COSMIC: COSV100096397;