ENST00000589578.5:c.2080G>C

Variant names:

• chr19-3637454-C-G
• rs552785133
• ENST00000589578.5:c.2080G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000589578.5(PIP5K1C):​c.2080G>C​(p.Ala694Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,535,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PIP5K1C ENST00000589578.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.142
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007458806).
• BP6: Variant 19-3637454-C-G is Benign according to our data. Variant chr19-3637454-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3045610.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589578.5. 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.1920+1430G>C		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.2080G>C	p.Ala694Pro	missense	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1430G>C		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000589578.5	TSL:1	c.2080G>C	p.Ala694Pro	missense	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*370G>C		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1430G>C		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152220 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000355 AC: 47 AN: 132484 AF XY: 0.000291

Gnomad AFR exome AF: 0.00458

Gnomad AMR exome AF: 0.000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000244

GnomAD4 exome AF: 0.000158 AC: 218 AN: 1383394 Hom.: 0 Cov.: 58 AF XY: 0.000149 AC XY: 102 AN XY: 682614

African (AFR) AF: 0.00544 AC: 172 AN: 31590

American (AMR) AF: 0.000420 AC: 15 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33610

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078786

Other (OTH) AF: 0.000449 AC: 26 AN: 57886

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152338 Hom.: 0 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74492

African (AFR) AF: 0.00589 AC: 245 AN: 41574

American (AMR) AF: 0.000849 AC: 13 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.00181

ExAC AF: 0.000171 AC: 3

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIP5K1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.29
DANN	Benign	0.29
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0075	T
PhyloP100		-0.14
Polyphen		0.0	B
Vest4		0.17
MVP		0.068
GERP RS		-2.4
gMVP		0.29
Mutation Taster		=97/3	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: rs552785133; hg19: chr19-3637452;