rs778236228

Variant names:

• chr9-136439223-C-G
• rs778236228
• NM_019892.6:c.197G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136439223-C-G
• chr9-136439223-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_019892.6(INPP5E):​c.197G>C​(p.Arg66Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,378,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: INPP5E NM_019892.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.50742 (below the threshold of 3.09). Trascript score misZ: -1.9401 (below the threshold of 3.09). GenCC associations: The gene is linked to Joubert syndrome with ocular defect, MORM syndrome, Joubert syndrome 1, Joubert syndrome, COACH syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.091013074).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.197G>C	p.Arg66Pro	missense	Exon 1 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.197G>C	p.Arg66Pro	missense	Exon 1 of 10	NP_001305431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.197G>C	p.Arg66Pro	missense	Exon 1 of 10	ENSP00000360777.3
	INPP5E	ENST00000676019.1		c.197G>C	p.Arg66Pro	missense	Exon 1 of 10	ENSP00000501984.1
	INPP5E	ENST00000635815.1	TSL:6	n.601G>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378664 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 679928

African (AFR) AF: 0.00 AC: 0 AN: 31130

American (AMR) AF: 0.00 AC: 0 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24882

East Asian (EAS) AF: 0.00 AC: 0 AN: 35430

South Asian (SAS) AF: 0.00 AC: 0 AN: 78898

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076282

Other (OTH) AF: 0.00 AC: 0 AN: 57508

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	4.3
DANN	Benign	0.74
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.90	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.27
Sift	Uncertain	0.013	D
Sift4G	Benign	0.24	T
Polyphen		0.11	B
Vest4		0.12
MutPred		0.16		Loss of helix (P = 0.0041)
MVP		0.57
MPC		0.51
ClinPred		0.20	T
GERP RS		-5.5
Varity_R		0.11
gMVP		0.21
Mutation Taster		=87/13	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: rs778236228; hg19: chr9-139333675;