19-10362257-A-G

Variant names:

• chr19-10362257-A-G
• rs280519
• NM_003331.5:c.1669+7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):​c.1669+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,613,552 control chromosomes in the GnomAD database, including 217,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20801 hom., cov: 31)
  • Exomes 𝑓: 0.52 (196719 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001091
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.11
• Publications: 113 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 (BayesDel_noAF=-0.91).
• BP6: Variant 19-10362257-A-G is Benign according to our data. Variant chr19-10362257-A-G is described in ClinVar as Benign. ClinVar VariationId is 259041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

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.1669+7T>C		splice_region intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.1669+7T>C		splice_region intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.1669+7T>C		splice_region intron	N/A	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.1669+7T>C		splice_region intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1114+7T>C		splice_region intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.1669+7T>C		splice_region intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78757 AN: 151768 Hom.: 20764 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.501 AC: 125522 AN: 250748 AF XY: 0.504

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.516 AC: 754252 AN: 1461666 Hom.: 196719 Cov.: 56 AF XY: 0.516 AC XY: 374865 AN XY: 727132

African (AFR) AF: 0.572 AC: 19152 AN: 33476

American (AMR) AF: 0.330 AC: 14763 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13535 AN: 26134

East Asian (EAS) AF: 0.520 AC: 20644 AN: 39684

South Asian (SAS) AF: 0.514 AC: 44317 AN: 86256

European-Finnish (FIN) AF: 0.536 AC: 28624 AN: 53358

Middle Eastern (MID) AF: 0.546 AC: 3148 AN: 5764

European-Non Finnish (NFE) AF: 0.520 AC: 577798 AN: 1111888

Other (OTH) AF: 0.534 AC: 32271 AN: 60396

GnomAD4 genome AF: 0.519 AC: 78856 AN: 151886 Hom.: 20801 Cov.: 31 AF XY: 0.516 AC XY: 38291 AN XY: 74206

African (AFR) AF: 0.565 AC: 23413 AN: 41408

American (AMR) AF: 0.409 AC: 6239 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1861 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3037 AN: 5146

South Asian (SAS) AF: 0.529 AC: 2546 AN: 4814

European-Finnish (FIN) AF: 0.524 AC: 5537 AN: 10562

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34452 AN: 67900

Other (OTH) AF: 0.508 AC: 1072 AN: 2112

Alfa AF: 0.507 Hom.: 23514

Bravo AF: 0.516

Asia WGS AF: 0.565 AC: 1959 AN: 3478

EpiCase AF: 0.515

EpiControl AF: 0.510

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Immunodeficiency 35 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.069
DANN	Benign	0.35
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.070		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: rs280519; hg19: chr19-10472933; COSMIC: COSV53384683; COSMIC: COSV53384683;