rs2230606

chr1-198706934-A-Cchr1-198706934-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002838.5(PTPRC):c.886A>C(p.Ile296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,603,636 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 32)
  • Exomes 𝑓: 0.018 (326 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.26

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002391249).
• BP6: Variant 1-198706934-A-C is Benign according to our data. Variant chr1-198706934-A-C is described in ClinVar as [Benign]. Clinvar id is 138848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-198706934-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2518/152318) while in subpopulation NFE AF= 0.0168 (1146/68026). AF 95% confidence interval is 0.016. There are 33 homozygotes in gnomad4. There are 1304 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRC	NM_002838.5	c.886A>C	p.Ile296Leu	missense_variant	9/33	ENST00000442510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRC	ENST00000442510.8	c.886A>C	p.Ile296Leu	missense_variant	9/33	1	NM_002838.5	A2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2509 AN: 152200 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0175 AC: 4389 AN: 251218 Hom.: 71 AF XY: 0.0177 AC XY: 2407 AN XY: 135790

Gnomad AFR exome AF: 0.00813

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0507

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0176 AC: 25512 AN: 1451318 Hom.: 326 Cov.: 30 AF XY: 0.0175 AC XY: 12656 AN XY: 722586

Gnomad4 AFR exome AF: 0.00873

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0513

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0474

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0165 AC: 2518 AN: 152318 Hom.: 33 Cov.: 32 AF XY: 0.0175 AC XY: 1304 AN XY: 74472

Gnomad4 AFR AF: 0.00835

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.000577

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0489

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0166 Hom.: 45

Bravo AF: 0.0134

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0159 AC: 1929

Asia WGS AF: 0.00780 AC: 28 AN: 3476

EpiCase AF: 0.0186

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2013

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 104 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.0010
Dann	Benign	0.65
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.073	T;T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
REVEL	Benign	0.043
Sift4G	Benign	0.40	T;T;T;T;T
Vest4		0.13, 0.059
MPC		0.17
ClinPred		0.0041	T
GERP RS		-9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.26

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: rs2230606; hg19: chr1-198676063;