rs34536443

Variant names:

• chr19-10352442-G-C
• rs34536443
• NM_003331.5:c.3310C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10352442-G-C
• chr19-10352442-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 7.51
• Publications: 331 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	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.: 69 Cov.: 32

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

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.: 30 AF XY: 0.0371 AC XY: 26862 AN XY: 723964

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: 1 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

GnomAD4 genome AF: 0.0278 AC: 4238 AN: 152278 Hom.: 69 Cov.: 32 AF XY: 0.0266 AC XY: 1983 AN XY: 74448

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: 0 AN: 5180

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4816

European-Finnish (FIN) AF: 0.0287 AC: 305 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0440 AC: 2990 AN: 68018

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0382 Hom.: 91

Bravo AF: 0.0262

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0403 AC: 347

ExAC AF: 0.0268 AC: 3256

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
1	-	2	Immunodeficiency 35 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.81
ClinPred		0.028	T
GERP RS		4.3
PromoterAI		0.019	Neutral
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)

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: rs34536443; hg19: chr19-10463118; COSMIC: COSV53387399; COSMIC: COSV53387399;