rs757369209

Variant names:

• chr6-43006514-C-A
• rs757369209
• NM_006245.4:c.157C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43006514-C-A
• chr6-43006514-C-G
• chr6-43006514-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_006245.4(PPP2R5D):​c.157C>A​(p.Pro53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P53S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 10 publications found

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]

PPP2R5D Gene-Disease associations (from GenCC):

• Hogue-Janssens syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 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 ClinVar as Pathogenic. ClinVar VariationId is 217455.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04306993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.157C>A	p.Pro53Thr	missense_variant	Exon 3 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.157C>A	p.Pro53Thr	missense_variant	Exon 3 of 16		NP_851307.1
PPP2R5D	NM_001270476.2	c.-297C>A		5_prime_UTR_variant	Exon 3 of 16		NP_001257405.1
PPP2R5D	NM_180977.3	c.28-420C>A		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>A	p.Pro53Thr	missense_variant	Exon 3 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.157C>A	p.Pro53Thr	missense_variant	Exon 3 of 16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249938 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.61
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.099
MutPred		0.21		Loss of catalytic residue at P52 (P = 0.0291);Loss of catalytic residue at P52 (P = 0.0291);.;
MVP		0.23
MPC		1.3
ClinPred		0.025	T
GERP RS		4.5
PromoterAI		0.19	Neutral
Varity_R		0.044
gMVP		0.30
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs757369209; hg19: chr6-42974252;