rs2304252

Variant names:

• chr19-10352559-G-A
• rs2304252
• NM_003331.5:c.3201-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10352559-G-A
• chr19-10352559-G-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.3201-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,457,160 control chromosomes in the GnomAD database, including 89 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 0.0026 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (82 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006729
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.171
• Publications: 1 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=-0.82).
• BP6: Variant 19-10352559-G-A is Benign according to our data. Variant chr19-10352559-G-A is described in ClinVar as Benign. ClinVar VariationId is 259044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0517 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.3201-8C>T		splice_region intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.3411-8C>T		splice_region intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.3282-8C>T		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.3201-8C>T		splice_region intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.2646-8C>T		splice_region intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.3201-8C>T		splice_region intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 152010 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0567

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00600 AC: 1146 AN: 190948 AF XY: 0.00589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000416

Gnomad EAS exome AF: 0.0597

Gnomad FIN exome AF: 0.00286

Gnomad NFE exome AF: 0.000828

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00227 AC: 2965 AN: 1305032 Hom.: 82 Cov.: 20 AF XY: 0.00231 AC XY: 1492 AN XY: 644708

African (AFR) AF: 0.0000673 AC: 2 AN: 29712

American (AMR) AF: 0.000114 AC: 4 AN: 35098

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 21 AN: 20732

East Asian (EAS) AF: 0.0545 AC: 2019 AN: 37036

South Asian (SAS) AF: 0.00264 AC: 193 AN: 73026

European-Finnish (FIN) AF: 0.00303 AC: 152 AN: 50212

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5236

European-Non Finnish (NFE) AF: 0.000411 AC: 411 AN: 999820

Other (OTH) AF: 0.00299 AC: 162 AN: 54160

GnomAD4 genome AF: 0.00258 AC: 392 AN: 152128 Hom.: 7 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74374

African (AFR) AF: 0.0000723 AC: 3 AN: 41506

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0570 AC: 295 AN: 5174

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.00315

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 35 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.45
DANN	Benign	0.54
PhyloP100		-0.17
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0
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: rs2304252; hg19: chr19-10463235; COSMIC: COSV53386878; COSMIC: COSV53386878;