rs769837511

Variant names:

• chr19-10352491-G-A
• rs769837511
• NM_003331.5:c.3261C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4 BP6_Moderate BP7

The NM_001385204.1(TYK2):​c.3471C>T​(p.Phe1157Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TYK2 NM_001385204.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0850
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.227).
• BP6: Variant 19-10352491-G-A is Benign according to our data. Variant chr19-10352491-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 468763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.085 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385204.1. 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.3261C>T	p.Phe1087Phe	synonymous	Exon 23 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.3471C>T	p.Phe1157Phe	synonymous	Exon 23 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.3342C>T	p.Phe1114Phe	synonymous	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.3261C>T	p.Phe1087Phe	synonymous	Exon 23 of 25	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.2706C>T	p.Phe902Phe	synonymous	Exon 19 of 21	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.3261C>T	p.Phe1087Phe	synonymous	Exon 23 of 25	ENSP00000436175.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244432 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722574

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.0000229 AC: 1 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.00 AC: 0 AN: 85524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107426

Other (OTH) AF: 0.00 AC: 0 AN: 60030

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 35 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		0.085
PromoterAI		-0.0084	Neutral

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: rs769837511; hg19: chr19-10463167; COSMIC: COSV99315564; COSMIC: COSV99315564;