chr5-134197777-G-GGAA

Position:

• chr5-134197777-G-GGAA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_002715.4(PPP2CA):​c.924_925insTTC​(p.Phe308dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2CA NM_002715.4 inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.44

Genes affected

PPP2CA (HGNC:9299): (protein phosphatase 2 catalytic subunit alpha) This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes an alpha isoform of the catalytic subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002715.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-134197777-G-GGAA is Pathogenic according to our data. Variant chr5-134197777-G-GGAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 620081.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2CA	NM_002715.4	c.924_925insTTC	p.Phe308dup	inframe_insertion	7/7	ENST00000481195.6
PPP2CA	NM_001355019.2	c.729_730insTTC	p.Phe243dup	inframe_insertion	7/7
PPP2CA	NR_149151.2	n.1179_1180insTTC		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2CA	ENST00000481195.6	c.924_925insTTC	p.Phe308dup	inframe_insertion	7/7	1	NM_002715.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Houge-Janssens syndrome 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jul 15, 2019	This variant is interpreted as a Likely pathogenic for Neurodevelopmental disorder and language delay with or without structural brain abnormalities, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PS3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 10, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622012; hg19: chr5-133533468;