6-43006514-C-G

Variant names:

• chr6-43006514-C-G
• NM_006245.4:c.157C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PM5 PP2 BP4_Strong

The NM_006245.4(PPP2R5D):​c.157C>G​(p.Pro53Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P53S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. 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. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-43006514-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the PPP2R5D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 3.6476 (above the threshold of 3.09). Trascript score misZ: 4.9069 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, syndromic intellectual disability, Hogue-Janssens syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05301857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.157C>G	p.Pro53Ala	missense_variant	Exon 3 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.157C>G	p.Pro53Ala	missense_variant	Exon 3 of 16		NP_851307.1
PPP2R5D	NM_001270476.2	c.-297C>G		5_prime_UTR_variant	Exon 3 of 16		NP_001257405.1
PPP2R5D	NM_180977.3	c.28-420C>G		intron_variant	Intron 1 of 13		NP_851308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.157C>G	p.Pro53Ala	missense_variant	Exon 3 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.157C>G	p.Pro53Ala	missense_variant	Exon 3 of 16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.23
MutPred		0.22		Loss of glycosylation at P53 (P = 0.0048);Loss of glycosylation at P53 (P = 0.0048);.;
MVP		0.25
MPC		1.1
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.026
gMVP		0.26

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42974252;