19-10357771-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003331.5(TYK2):​c.2459C>A​(p.Pro820His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,609,950 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 13 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 12 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

4
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.90
Variant links:
Genes affected
TYK2 (HGNC:12440): (tyrosine kinase 2) This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0072814524).
BP6
Variant 19-10357771-G-T is Benign according to our data. Variant chr19-10357771-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 536652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00794 (1210/152348) while in subpopulation AFR AF= 0.0268 (1116/41576). AF 95% confidence interval is 0.0255. There are 13 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TYK2NM_003331.5 linkc.2459C>A p.Pro820His missense_variant Exon 17 of 25 ENST00000525621.6 NP_003322.3 P29597A0A024R7E4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TYK2ENST00000525621.6 linkc.2459C>A p.Pro820His missense_variant Exon 17 of 25 1 NM_003331.5 ENSP00000431885.1 P29597

Frequencies

GnomAD3 genomes
AF:
0.00792
AC:
1206
AN:
152230
Hom.:
13
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0268
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00537
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00178
AC:
429
AN:
241360
Hom.:
6
AF XY:
0.00138
AC XY:
181
AN XY:
131258
show subpopulations
Gnomad AFR exome
AF:
0.0245
Gnomad AMR exome
AF:
0.00121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000462
Gnomad OTH exome
AF:
0.00119
GnomAD4 exome
AF:
0.000729
AC:
1063
AN:
1457602
Hom.:
12
Cov.:
31
AF XY:
0.000607
AC XY:
440
AN XY:
724806
show subpopulations
Gnomad4 AFR exome
AF:
0.0262
Gnomad4 AMR exome
AF:
0.00152
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00178
GnomAD4 genome
AF:
0.00794
AC:
1210
AN:
152348
Hom.:
13
Cov.:
33
AF XY:
0.00758
AC XY:
565
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.0268
Gnomad4 AMR
AF:
0.00536
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00233
Hom.:
3
Bravo
AF:
0.00875
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.0247
AC:
109
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00209
AC:
253
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Immunodeficiency 35 Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Nov 22, 2017
GeneDx
Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.45
T;D;T;.
Eigen
Benign
0.12
Eigen_PC
Benign
-0.029
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.83
T;T;.;T
MetaRNN
Benign
0.0073
T;T;T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.8
L;.;L;.
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-3.5
D;D;D;D
REVEL
Benign
0.28
Sift
Benign
0.030
D;D;D;D
Sift4G
Uncertain
0.033
D;D;D;T
Polyphen
0.95
P;.;P;D
Vest4
0.43
MVP
0.81
MPC
0.97
ClinPred
0.039
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.44

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34046749; hg19: chr19-10468447; API