Genetic Variant NM_002838.5:c.177C>G (chr1-198696788-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002838.5(PTPRC):c.177C>G(p.Pro59Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,926 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P59P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0083 ( 8 hom., cov: 32)

Exomes 𝑓: 0.013 ( 169 hom. )

Consequence

PTPRC
NM_002838.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.527

Publications

81 publications found

Variant links:

Genes affected

PTPRC (HGNC:9666): (protein tyrosine phosphatase receptor type C) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitosis, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus is classified as a receptor type PTP. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jun 2012]

PTPRC Gene-Disease associations (from GenCC):

immunodeficiency 104
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
T-B+ severe combined immunodeficiency due to CD45 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PTPRC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 1-198696788-C-G is Benign according to our data. Variant chr1-198696788-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.527 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00833 (1268/152258) while in subpopulation NFE AF = 0.0138 (937/68020). AF 95% confidence interval is 0.013. There are 8 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002838.5. 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
	PTPRC	NM_002838.5	MANE Select	c.177C>G	p.Pro59Pro	synonymous	Exon 4 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.100+4415C>G		intron	N/A	NP_563578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.177C>G	p.Pro59Pro	synonymous	Exon 4 of 33	ENSP00000411355.3
PTPRC	ENST00000529828.5	TSL:1	n.177C>G		non_coding_transcript_exon	Exon 4 of 22	ENSP00000469141.1
PTPRC	ENST00000348564.12	TSL:1	c.100+4415C>G		intron	N/A	ENSP00000306782.7

Frequencies

GnomAD3 genomes

AF:

0.00833

AC:

1268

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00877

AC:

2205

AN:

251456

AF XY:

0.00926

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.00652

GnomAD4 exome

AF:

0.0127

AC:

18551

AN:

1461668

Hom.:

169

Cov.:

AF XY:

0.0128

AC XY:

9340

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33476

American (AMR)

AF:

0.00407

AC:

182

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0116

AC:

1000

AN:

86252

European-Finnish (FIN)

AF:

0.00537

AC:

287

AN:

53418

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0147

AC:

16306

AN:

1111814

Other (OTH)

AF:

0.0106

AC:

638

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1028

2056

3084

4112

5140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

628

1256

1884

2512

3140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00833

AC:

1268

AN:

152258

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

595

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00258

AC:

107

AN:

41536

American (AMR)

AF:

0.00719

AC:

110

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00726

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0138

AC:

937

AN:

68020

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.00765

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTPRC: BP4, BP7, BS1, BS2

not specified

Benign:1

Jul 15, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Immunodeficiency 105

Benign:1

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTPRC POLYMORPHISM

Benign:1

Jun 03, 2011

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

Immunodeficiency 104

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.4

(source)

DANN

Benign

0.62

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over