chr19-3633461-C-CG

Variant names:

• chr19-3633461-C-CG
• rs748532409
• NM_012398.3:c.1979dupC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_012398.3(PIP5K1C):​c.1979dupC​(p.Ala661GlyfsTer81) variant causes a frameshift change. The variant allele was found at a frequency of 0.000351 in 1,501,830 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PIP5K1C NM_012398.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39
• Publications: 3 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.014 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

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.1979dupC	p.Ala661GlyfsTer81	frameshift	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-293dupC		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.1979dupC	p.Ala661GlyfsTer81	frameshift	Exon 17 of 18	ENSP00000335333.3	O60331-1
	PIP5K1C	ENST00000876625.1		c.2096dupC	p.Ala700GlyfsTer81	frameshift	Exon 18 of 19	ENSP00000546684.1
	PIP5K1C	ENST00000967141.1		c.2081dupC	p.Ala695GlyfsTer81	frameshift	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152084 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000294 AC: 46 AN: 156664 AF XY: 0.000319

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000257

Gnomad ASJ exome AF: 0.000585

Gnomad EAS exome AF: 0.0000748

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.000357 AC: 482 AN: 1349628 Hom.: 0 Cov.: 31 AF XY: 0.000343 AC XY: 227 AN XY: 661000

African (AFR) AF: 0.0000999 AC: 3 AN: 30036

American (AMR) AF: 0.000388 AC: 12 AN: 30954

Ashkenazi Jewish (ASJ) AF: 0.000100 AC: 2 AN: 19902

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37612

South Asian (SAS) AF: 0.000294 AC: 20 AN: 68074

European-Finnish (FIN) AF: 0.000375 AC: 18 AN: 48056

Middle Eastern (MID) AF: 0.00115 AC: 6 AN: 5216

European-Non Finnish (NFE) AF: 0.000372 AC: 392 AN: 1054478

Other (OTH) AF: 0.000470 AC: 26 AN: 55300

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74418

African (AFR) AF: 0.000265 AC: 11 AN: 41530

American (AMR) AF: 0.000916 AC: 14 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000314

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=13/187	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs748532409; hg19: chr19-3633459; COSMIC: COSV58951217; COSMIC: COSV58951217;