19-3633275-G-C

Variant names:

• chr19-3633275-G-C
• rs542690
• NM_012398.3:c.2005-106C>G

Variant summary

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

The NM_012398.3(PIP5K1C):​c.2005-106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 680,774 control chromosomes in the GnomAD database, including 92,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17939 hom., cov: 33)
  • Exomes 𝑓: 0.50 (74398 hom.)
• Consequence: PIP5K1C NM_012398.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-3633275-G-C is Benign according to our data. Variant chr19-3633275-G-C is described in ClinVar as Benign. ClinVar VariationId is 1245619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

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.2005-106C>G		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-106C>G		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.2005-106C>G		intron	N/A	ENSP00000335333.3	O60331-1
	PIP5K1C	ENST00000876625.1		c.2122-106C>G		intron	N/A	ENSP00000546684.1
	PIP5K1C	ENST00000967141.1		c.2107-106C>G		intron	N/A	ENSP00000637200.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69664 AN: 151962 Hom.: 17942 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.0700

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.495

GnomAD4 exome AF: 0.504 AC: 266649 AN: 528694 Hom.: 74398 Cov.: 6 AF XY: 0.499 AC XY: 140105 AN XY: 280962

African (AFR) AF: 0.297 AC: 4310 AN: 14500

American (AMR) AF: 0.329 AC: 9320 AN: 28332

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 8867 AN: 16494

East Asian (EAS) AF: 0.0412 AC: 1286 AN: 31248

South Asian (SAS) AF: 0.317 AC: 17309 AN: 54582

European-Finnish (FIN) AF: 0.593 AC: 27159 AN: 45826

Middle Eastern (MID) AF: 0.449 AC: 1703 AN: 3794

European-Non Finnish (NFE) AF: 0.597 AC: 182241 AN: 305108

Other (OTH) AF: 0.502 AC: 14454 AN: 28810

GnomAD4 genome AF: 0.458 AC: 69669 AN: 152080 Hom.: 17939 Cov.: 33 AF XY: 0.452 AC XY: 33597 AN XY: 74358

African (AFR) AF: 0.296 AC: 12297 AN: 41508

American (AMR) AF: 0.369 AC: 5644 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1836 AN: 3462

East Asian (EAS) AF: 0.0700 AC: 361 AN: 5158

South Asian (SAS) AF: 0.303 AC: 1460 AN: 4822

European-Finnish (FIN) AF: 0.594 AC: 6299 AN: 10608

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40167 AN: 67924

Other (OTH) AF: 0.490 AC: 1033 AN: 2110

Alfa AF: 0.533 Hom.: 2820

Bravo AF: 0.436

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.2
DANN	Benign	0.69
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs542690; hg19: chr19-3633273; COSMIC: COSV58951956; COSMIC: COSV58951956;