chr12-70534620-C-T

Variant names:

• chr12-70534620-C-T
• rs748022415
• NM_001109754.4:c.6236G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001109754.4(PTPRB):​c.6236G>A​(p.Arg2079His) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2079C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PTPRB NM_001109754.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• Publications: 1 publications found

Genes affected

PTPRB (HGNC:9665): (protein tyrosine phosphatase receptor type B) 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, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and one intracytoplasmic catalytic domain, thus belongs to receptor type PTP. The extracellular region of this PTP is composed of multiple fibronectin type_III repeats, which was shown to interact with neuronal receptor and cell adhesion molecules, such as contactin and tenascin C. This protein was also found to interact with sodium channels, and thus may regulate sodium channels by altering tyrosine phosphorylation status. The functions of the interaction partners of this protein implicate the roles of this PTP in cell adhesion, neurite growth, and neuronal differentiation. Alternate transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

PTPRB-AS1 (HGNC:58150):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRB	NM_001109754.4	MANE Select	c.6236G>A	p.Arg2079His	missense	Exon 31 of 34	NP_001103224.1	P23467-3
	PTPRB	NM_001330204.2		c.5972G>A	p.Arg1991His	missense	Exon 30 of 33	NP_001317133.1	F8VU56
	PTPRB	NM_002837.6		c.5582G>A	p.Arg1861His	missense	Exon 29 of 32	NP_002828.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRB	ENST00000334414.11	TSL:1 MANE Select	c.6236G>A	p.Arg2079His	missense	Exon 31 of 34	ENSP00000334928.6	P23467-3
	PTPRB	ENST00000261266.9	TSL:1	c.5582G>A	p.Arg1861His	missense	Exon 29 of 32	ENSP00000261266.5	P23467-1
	PTPRB	ENST00000538708.5	TSL:1	c.5312G>A	p.Arg1771His	missense	Exon 28 of 31	ENSP00000438927.1	P23467-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000812 AC: 2 AN: 246428 AF XY: 0.00000748

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460358 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 726296

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85842

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111334

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.67		Gain of catalytic residue at Y1995 (P = 0.0095)
MVP		0.92
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.67
Mutation Taster		=42/58	disease causing

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: rs748022415; hg19: chr12-70928400; COSMIC: COSV108089253; COSMIC: COSV108089253;