NM_003331.5:c.3200+122G>C

Variant names:

• chr19-10352804-C-G
• rs280496
• NM_003331.5:c.3200+122G>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.3200+122G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,324,388 control chromosomes in the GnomAD database, including 43,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7209 hom., cov: 32)
  • Exomes 𝑓: 0.24 (35858 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94
• Publications: 7 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=-0.86).
• BP6: Variant 19-10352804-C-G is Benign according to our data. Variant chr19-10352804-C-G is described in ClinVar as Benign. ClinVar VariationId is 673301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 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.3200+122G>C		intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.3410+122G>C		intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.3281+122G>C		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.3200+122G>C		intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.2645+122G>C		intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.3200+122G>C		intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43797 AN: 152082 Hom.: 7180 Cov.: 32

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.241 AC: 282894 AN: 1172188 Hom.: 35858 AF XY: 0.241 AC XY: 139260 AN XY: 578128

African (AFR) AF: 0.461 AC: 12328 AN: 26730

American (AMR) AF: 0.137 AC: 3953 AN: 28844

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 4437 AN: 18572

East Asian (EAS) AF: 0.0844 AC: 3049 AN: 36146

South Asian (SAS) AF: 0.249 AC: 16259 AN: 65250

European-Finnish (FIN) AF: 0.279 AC: 9370 AN: 33562

Middle Eastern (MID) AF: 0.290 AC: 979 AN: 3372

European-Non Finnish (NFE) AF: 0.242 AC: 220064 AN: 910040

Other (OTH) AF: 0.251 AC: 12455 AN: 49672

GnomAD4 genome AF: 0.288 AC: 43876 AN: 152200 Hom.: 7209 Cov.: 32 AF XY: 0.286 AC XY: 21284 AN XY: 74416

African (AFR) AF: 0.447 AC: 18557 AN: 41512

American (AMR) AF: 0.188 AC: 2880 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3468

East Asian (EAS) AF: 0.0852 AC: 441 AN: 5178

South Asian (SAS) AF: 0.257 AC: 1241 AN: 4832

European-Finnish (FIN) AF: 0.288 AC: 3052 AN: 10598

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16041 AN: 67996

Other (OTH) AF: 0.272 AC: 575 AN: 2114

Alfa AF: 0.115 Hom.: 174

Bravo AF: 0.287

Asia WGS AF: 0.228 AC: 791 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.77
DANN	Benign	0.25
PhyloP100		-1.9
PromoterAI		0.0067	Neutral
Mutation Taster		=100/0	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: rs280496; hg19: chr19-10463480; COSMIC: COSV53385827; COSMIC: COSV53385827;