9-101594926-G-C

Variant names:

• chr9-101594926-G-C
• rs140910583
• NM_147180.4:c.-5C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147180.4(PPP3R2):​c.-5C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,597,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: PPP3R2 NM_147180.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.783

Genes affected

PPP3R2 (HGNC:9318): (protein phosphatase 3 regulatory subunit B, beta) Predicted to enable calcium ion binding activity and calcium-dependent protein serine/threonine phosphatase regulator activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within penetration of zona pellucida. Predicted to be located in sperm mitochondrial sheath. Predicted to be part of calcineurin complex. [provided by Alliance of Genome Resources, Apr 2022]

GRIN3A (HGNC:16767): (glutamate ionotropic receptor NMDA type subunit 3A) This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptors, which belong to the superfamily of glutamate-regulated ion channels, and function in physiological and pathological processes in the central nervous system. This subunit shows greater than 90% identity to the corresponding subunit in rat. Studies in the knockout mouse deficient in this subunit suggest that this gene may be involved in the development of synaptic elements by modulating NMDA receptor activity. [provided by RefSeq, Jul 2008]

LOC105376186 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08460292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3R2	NM_147180.4	c.-5C>G		5_prime_UTR_variant	Exon 1 of 1	ENST00000374806.2	NP_671709.2
GRIN3A	NM_133445.3	c.2767-15566C>G		intron_variant	Intron 6 of 8	ENST00000361820.6	NP_597702.2
LOC105376186	XR_001746863.2	n.-48G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3R2	ENST00000374806.2	c.-5C>G		5_prime_UTR_variant	Exon 1 of 1	6	NM_147180.4	ENSP00000363939.2
PPP3R2	ENST00000636434.1	c.-118C>G		5_prime_UTR_variant	Exon 1 of 2	1		ENSP00000490051.1
GRIN3A	ENST00000361820.6	c.2767-15566C>G		intron_variant	Intron 6 of 8	1	NM_133445.3	ENSP00000355155.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000516 AC: 12 AN: 232562 Hom.: 0 AF XY: 0.0000471 AC XY: 6 AN XY: 127430

Gnomad AFR exome AF: 0.000472

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000663

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000277 AC: 40 AN: 1445232 Hom.: 0 Cov.: 31 AF XY: 0.0000264 AC XY: 19 AN XY: 719238

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000663 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>G (p.S2C) alteration is located in exon 1 (coding exon 1) of the PPP3R2 gene. This alteration results from a C to G substitution at nucleotide position 5, causing the serine (S) at amino acid position 2 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.95
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.069
Sift	Benign	0.068	T
Sift4G	Uncertain	0.035	D
Vest4		0.11
MVP		0.63
MPC		0.34
ClinPred		0.025	T
GERP RS		1.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs140910583; hg19: chr9-104357208;