rs687

Variant names:

• chr2-68188635-G-A
• rs687
• NM_000945.4:c.99C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000945.4(PPP3R1):​c.99C>T​(p.Asp33Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.429 in 1,611,810 control chromosomes in the GnomAD database, including 152,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16010 hom., cov: 31)
  • Exomes 𝑓: 0.43 (136001 hom.)
• Consequence: PPP3R1 NM_000945.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.12
• Publications: 25 publications found

Genes affected

PPP3R1 (HGNC:9317): (protein phosphatase 3 regulatory subunit B, alpha) Enables cyclosporin A binding activity; phosphatase binding activity; and protein domain specific binding activity. Involved in calcineurin-NFAT signaling cascade and positive regulation of transcription by RNA polymerase II. Part of calcineurin complex. Implicated in Alzheimer's disease and dilated cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000273398 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-68188635-G-A is Benign according to our data. Variant chr2-68188635-G-A is described in ClinVar as Benign. ClinVar VariationId is 1181494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000945.4. 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
	PPP3R1	NM_000945.4	MANE Select	c.99C>T	p.Asp33Asp	synonymous	Exon 3 of 6	NP_000936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3R1	ENST00000234310.8	TSL:1 MANE Select	c.99C>T	p.Asp33Asp	synonymous	Exon 3 of 6	ENSP00000234310.3
	ENSG00000273398	ENST00000406334.3	TSL:2	n.69C>T		non_coding_transcript_exon	Exon 4 of 15	ENSP00000384974.3
	PPP3R1	ENST00000409752.5	TSL:3	c.156C>T	p.Asp52Asp	synonymous	Exon 3 of 6	ENSP00000387216.1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69109 AN: 151774 Hom.: 15994 Cov.: 31

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.473 AC: 117015 AN: 247438 AF XY: 0.480

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.514

Gnomad FIN exome AF: 0.538

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.426 AC: 621984 AN: 1459918 Hom.: 136001 Cov.: 37 AF XY: 0.432 AC XY: 314112 AN XY: 726282

African (AFR) AF: 0.497 AC: 16592 AN: 33404

American (AMR) AF: 0.471 AC: 20977 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11944 AN: 26086

East Asian (EAS) AF: 0.475 AC: 18794 AN: 39562

South Asian (SAS) AF: 0.632 AC: 54362 AN: 86024

European-Finnish (FIN) AF: 0.535 AC: 28536 AN: 53334

Middle Eastern (MID) AF: 0.529 AC: 3046 AN: 5754

European-Non Finnish (NFE) AF: 0.397 AC: 440779 AN: 1110910

Other (OTH) AF: 0.447 AC: 26954 AN: 60294

GnomAD4 genome AF: 0.455 AC: 69174 AN: 151892 Hom.: 16010 Cov.: 31 AF XY: 0.464 AC XY: 34425 AN XY: 74238

African (AFR) AF: 0.492 AC: 20375 AN: 41420

American (AMR) AF: 0.477 AC: 7289 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1596 AN: 3468

East Asian (EAS) AF: 0.506 AC: 2611 AN: 5162

South Asian (SAS) AF: 0.618 AC: 2981 AN: 4824

European-Finnish (FIN) AF: 0.538 AC: 5661 AN: 10516

Middle Eastern (MID) AF: 0.566 AC: 164 AN: 290

European-Non Finnish (NFE) AF: 0.401 AC: 27223 AN: 67914

Other (OTH) AF: 0.478 AC: 1008 AN: 2108

Alfa AF: 0.422 Hom.: 10093

Bravo AF: 0.447

Asia WGS AF: 0.586 AC: 2032 AN: 3472

EpiCase AF: 0.418

EpiControl AF: 0.411

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		5.1
Mutation Taster		=91/9	polymorphism (auto)

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: rs687; hg19: chr2-68415767; COSMIC: COSV52246314;