rs12720319

Variant names:

• chr19-10354244-A-C
• rs12720319
• NM_003331.5:c.2716-10T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10354244-A-C
• chr19-10354244-A-G

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.2716-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,610,004 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (195 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (159 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Scores: Splicing: ADA: 0.0009037
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.998
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-10354244-A-C is Benign according to our data. Variant chr19-10354244-A-C is described in ClinVar as Benign. ClinVar VariationId is 327936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.094 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.2716-10T>G		intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.2926-10T>G		intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.2797-10T>G		intron	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.2716-10T>G		intron	N/A	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.2161-10T>G		intron	N/A	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.2716-10T>G		intron	N/A	ENSP00000436175.2

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4232 AN: 151990 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00692 AC: 1710 AN: 247206 AF XY: 0.00501

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00269 AC: 3918 AN: 1457896 Hom.: 159 Cov.: 33 AF XY: 0.00231 AC XY: 1673 AN XY: 725396

African (AFR) AF: 0.0956 AC: 3197 AN: 33446

American (AMR) AF: 0.00530 AC: 237 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50600

Middle Eastern (MID) AF: 0.00286 AC: 14 AN: 4894

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111932

Other (OTH) AF: 0.00616 AC: 371 AN: 60274

GnomAD4 genome AF: 0.0280 AC: 4254 AN: 152108 Hom.: 195 Cov.: 32 AF XY: 0.0265 AC XY: 1967 AN XY: 74362

African (AFR) AF: 0.0965 AC: 4002 AN: 41486

American (AMR) AF: 0.0131 AC: 200 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67994

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0188 Hom.: 37

Bravo AF: 0.0315

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 35 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.081
DANN	Benign	0.31
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.11		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: rs12720319; hg19: chr19-10464920;