Genetic Variant NM_003331.5:c.3310C>G (chr19-10352442-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003331.5(TYK2):c.3310C>G(p.Pro1104Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,607,098 control chromosomes in the GnomAD database, including 1,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 69 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1164 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 7.51

Publications

331 publications found

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]

TYK2 Gene-Disease associations (from GenCC):

immunodeficiency 35
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009062827).

BP6

Variant 19-10352442-G-C is Benign according to our data. Variant chr19-10352442-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0278 (4238/152278) while in subpopulation NFE AF = 0.044 (2990/68018). AF 95% confidence interval is 0.0426. There are 69 homozygotes in GnomAd4. There are 1983 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.3310C>G	p.Pro1104Ala	missense	Exon 23 of 25	NP_003322.3
TYK2	NM_001385204.1		c.3520C>G	p.Pro1174Ala	missense	Exon 23 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.3391C>G	p.Pro1131Ala	missense	Exon 24 of 26	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.3310C>G	p.Pro1104Ala	missense	Exon 23 of 25	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.2755C>G	p.Pro919Ala	missense	Exon 19 of 21	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.3310C>G	p.Pro1104Ala	missense	Exon 23 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes

AF:

0.0278

AC:

4235

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00914

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0287

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0268

AC:

6632

AN:

247438

AF XY:

0.0271

show subpopulations

Gnomad AFR exome

AF:

0.00712

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0381

AC:

55360

AN:

1454820

Hom.:

1164

Cov.:

AF XY:

0.0371

AC XY:

26862

AN XY:

723964

show subpopulations

African (AFR)

AF:

0.00703

AC:

234

AN:

33284

American (AMR)

AF:

0.0123

AC:

544

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

792

AN:

25930

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.0115

AC:

988

AN:

85890

European-Finnish (FIN)

AF:

0.0300

AC:

1596

AN:

53222

Middle Eastern (MID)

AF:

0.0197

AC:

112

AN:

5690

European-Non Finnish (NFE)

AF:

0.0445

AC:

49298

AN:

1106976

Other (OTH)

AF:

0.0299

AC:

1795

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2227

4455

6682

8910

11137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1876

3752

5628

7504

9380

<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:

0.0278

AC:

4238

AN:

152278

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1983

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00912

AC:

379

AN:

41572

American (AMR)

AF:

0.0214

AC:

327

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

115

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0118

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0287

AC:

305

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0440

AC:

2990

AN:

68018

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

216

431

647

862

1078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0382

Hom.:

Bravo

AF:

0.0262

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0527

AC:

203

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0403

AC:

347

ExAC

AF:

0.0268

AC:

3256

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Immunodeficiency 35 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0091

MetaSVM

Uncertain

-0.060

MutationAssessor

Benign

1.4

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.22

MPC

0.81

ClinPred

0.028

GERP RS

4.3

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.68

gMVP

0.67

Mutation Taster

=79/21

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over