rs561346539

Variant names:

• chr19-3637554-C-G
• rs561346539
• ENST00000589578.5:c.1980G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-3637554-C-G
• chr19-3637554-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001300849.2(PIP5K1C):​c.1980G>C​(p.Thr660Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,530,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PIP5K1C NM_001300849.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.367
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-3637554-C-G is Benign according to our data. Variant chr19-3637554-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3051894.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.367 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300849.2. 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+1330G>C		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.1980G>C	p.Thr660Thr	synonymous	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1330G>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.1980G>C	p.Thr660Thr	synonymous	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*270G>C		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1330G>C		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 189 AN: 150250 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000463

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: 0.0000148

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000239 AC: 32 AN: 134106 AF XY: 0.000178

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.000245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 164 AN: 1380588 Hom.: 0 Cov.: 57 AF XY: 0.0000866 AC XY: 59 AN XY: 681070

African (AFR) AF: 0.00444 AC: 140 AN: 31530

American (AMR) AF: 0.000225 AC: 8 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35556

South Asian (SAS) AF: 0.00 AC: 0 AN: 79168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1076748

Other (OTH) AF: 0.000225 AC: 13 AN: 57686

GnomAD4 genome AF: 0.00126 AC: 189 AN: 150372 Hom.: 0 Cov.: 31 AF XY: 0.00117 AC XY: 86 AN XY: 73410

African (AFR) AF: 0.00433 AC: 178 AN: 41146

American (AMR) AF: 0.000462 AC: 7 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10198

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67478

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.00153

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PIP5K1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.80
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs561346539; hg19: chr19-3637552;