rs2292006

Variant names:

• chr3-171140617-T-G
• rs2292006
• NM_015028.4:c.1222-108A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015028.4(TNIK):​c.1222-108A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 955,710 control chromosomes in the GnomAD database, including 265,984 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (42655 hom., cov: 31)
  • Exomes 𝑓: 0.74 (223329 hom.)
• Consequence: TNIK NM_015028.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 5 publications found

Genes affected

TNIK (HGNC:30765): (TRAF2 and NCK interacting kinase) Wnt signaling plays important roles in carcinogenesis and embryonic development. The protein encoded by this gene is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. Mutations in this gene are associated with an autosomal recessive form of cognitive disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

TNIK Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 54

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105374216 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015028.4. 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
	TNIK	NM_015028.4	MANE Select	c.1222-108A>C		intron	N/A	NP_055843.1	Q9UKE5-1
	TNIK	NM_001161560.3		c.1222-108A>C		intron	N/A	NP_001155032.1	Q9UKE5-4
	TNIK	NM_001161561.3		c.1222-108A>C		intron	N/A	NP_001155033.1	Q9UKE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	ENST00000436636.7	TSL:1 MANE Select	c.1222-108A>C		intron	N/A	ENSP00000399511.2	Q9UKE5-1
	TNIK	ENST00000284483.12	TSL:1	c.1222-108A>C		intron	N/A	ENSP00000284483.8	Q9UKE5-4
	TNIK	ENST00000357327.9	TSL:1	c.1222-108A>C		intron	N/A	ENSP00000349880.5	Q9UKE5-2

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113440 AN: 151856 Hom.: 42621 Cov.: 31

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.707

GnomAD4 exome AF: 0.743 AC: 597493 AN: 803736 Hom.: 223329 AF XY: 0.741 AC XY: 313918 AN XY: 423778

African (AFR) AF: 0.740 AC: 15066 AN: 20362

American (AMR) AF: 0.782 AC: 31012 AN: 39654

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 15249 AN: 20582

East Asian (EAS) AF: 0.572 AC: 20644 AN: 36086

South Asian (SAS) AF: 0.709 AC: 49291 AN: 69480

European-Finnish (FIN) AF: 0.838 AC: 32756 AN: 39092

Middle Eastern (MID) AF: 0.751 AC: 3323 AN: 4422

European-Non Finnish (NFE) AF: 0.750 AC: 401575 AN: 535320

Other (OTH) AF: 0.738 AC: 28577 AN: 38738

GnomAD4 genome AF: 0.747 AC: 113529 AN: 151974 Hom.: 42655 Cov.: 31 AF XY: 0.749 AC XY: 55618 AN XY: 74256

African (AFR) AF: 0.742 AC: 30732 AN: 41404

American (AMR) AF: 0.752 AC: 11488 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2539 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2866 AN: 5142

South Asian (SAS) AF: 0.720 AC: 3464 AN: 4812

European-Finnish (FIN) AF: 0.850 AC: 9000 AN: 10588

Middle Eastern (MID) AF: 0.733 AC: 214 AN: 292

European-Non Finnish (NFE) AF: 0.750 AC: 50947 AN: 67966

Other (OTH) AF: 0.702 AC: 1482 AN: 2112

Alfa AF: 0.740 Hom.: 105915

Bravo AF: 0.738

Asia WGS AF: 0.639 AC: 2225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.44
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2292006; hg19: chr3-170858406; COSMIC: COSV52677070;