NM_019892.6:c.1791G>C

Variant names:

• chr9-136430288-C-G
• rs10870182
• NM_019892.6:c.1791G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_019892.6(INPP5E):​c.1791G>C​(p.Pro597Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,551,406 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P597P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (81 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -4.81
• Publications: 16 publications found

Genes affected

INPP5E (HGNC:21474): (inositol polyphosphate-5-phosphatase E) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

INPP5E Gene-Disease associations (from GenCC):

• Joubert syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Orphanet
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 9-136430288-C-G is Benign according to our data. Variant chr9-136430288-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129271.
• BP7: Synonymous conserved (PhyloP=-4.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00494 (753/152322) while in subpopulation NFE AF = 0.00879 (598/68014). AF 95% confidence interval is 0.00821. There are 2 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019892.6. 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
	INPP5E	NM_019892.6	MANE Select	c.1791G>C	p.Pro597Pro	synonymous	Exon 9 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1788G>C	p.Pro596Pro	synonymous	Exon 9 of 10	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1791G>C	p.Pro597Pro	synonymous	Exon 9 of 10	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1812G>C	p.Pro604Pro	synonymous	Exon 9 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1788G>C	p.Pro596Pro	synonymous	Exon 9 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00417 AC: 653 AN: 156470 AF XY: 0.00407

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000469

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00848

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00872 AC: 12207 AN: 1399084 Hom.: 81 Cov.: 36 AF XY: 0.00834 AC XY: 5754 AN XY: 690040

African (AFR) AF: 0.00174 AC: 55 AN: 31602

American (AMR) AF: 0.00205 AC: 73 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.000675 AC: 17 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35752

South Asian (SAS) AF: 0.00173 AC: 137 AN: 79236

European-Finnish (FIN) AF: 0.00127 AC: 62 AN: 48940

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5696

European-Non Finnish (NFE) AF: 0.0105 AC: 11325 AN: 1078986

Other (OTH) AF: 0.00912 AC: 529 AN: 57996

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00448 AC XY: 334 AN XY: 74478

African (AFR) AF: 0.00209 AC: 87 AN: 41576

American (AMR) AF: 0.00255 AC: 39 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00879 AC: 598 AN: 68014

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00136 Hom.: 128

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Joubert syndrome (1)
-	1	-	Joubert syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.037
DANN	Benign	0.60
PhyloP100		-4.8
Mutation Taster		=99/1	polymorphism

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: rs10870182; hg19: chr9-139324740; COSMIC: COSV108207388;