rs1555719851

Variant names:

• chr19-10365750-GG-AA
• rs1555719851
• NM_003331.5:c.777_778delCCinsTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6 BP7

The NM_003331.5(TYK2):​c.777_778delCCinsTT​(p.261) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYK2 NM_003331.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.11
• 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.

• BP6: Variant 19-10365750-GG-AA is Benign according to our data. Variant chr19-10365750-GG-AA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536655.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.777_778delCCinsTT	p.261	synonymous	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.777_778delCCinsTT	p.261	synonymous	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.777_778delCCinsTT	p.261	synonymous	N/A	NP_001372132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.777_778delCCinsTT	p.261	synonymous	N/A	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.222_223delCCinsTT	p.76	synonymous	N/A	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.777_778delCCinsTT	p.261	synonymous	N/A	ENSP00000436175.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 35 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555719851; hg19: chr19-10476426;