2-58159865-C-T

Variant names:

• chr2-58159865-C-T
• rs3732136
• ENST00000435505.6:c.*172C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000435505.6(VRK2):​c.*172C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,600,198 control chromosomes in the GnomAD database, including 82,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (18385 hom., cov: 32)
  • Exomes 𝑓: 0.28 (64375 hom.)
• Consequence: VRK2 ENST00000435505.6 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.773
• Publications: 26 publications found

Genes affected

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

FANCL Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group L

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-58159865-C-T is Benign according to our data. Variant chr2-58159865-C-T is described in ClinVar as [Benign]. Clinvar id is 1274642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK2	NM_006296.7	c.*172C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000340157.9	NP_006287.2
FANCL	NM_018062.4	c.1093-65G>A		intron_variant	Intron 13 of 13	ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK2	ENST00000340157.9	c.*172C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_006296.7	ENSP00000342381.4
FANCL	ENST00000233741.9	c.1093-65G>A		intron_variant	Intron 13 of 13	1	NM_018062.4	ENSP00000233741.5

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64600 AN: 151798 Hom.: 18332 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.284 AC: 411882 AN: 1448282 Hom.: 64375 Cov.: 32 AF XY: 0.281 AC XY: 202452 AN XY: 719978

African (AFR) AF: 0.848 AC: 27957 AN: 32972

American (AMR) AF: 0.279 AC: 12064 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6405 AN: 25796

East Asian (EAS) AF: 0.290 AC: 11456 AN: 39526

South Asian (SAS) AF: 0.240 AC: 20335 AN: 84764

European-Finnish (FIN) AF: 0.317 AC: 16393 AN: 51680

Middle Eastern (MID) AF: 0.223 AC: 1029 AN: 4610

European-Non Finnish (NFE) AF: 0.270 AC: 298078 AN: 1106032

Other (OTH) AF: 0.304 AC: 18165 AN: 59680

GnomAD4 genome AF: 0.426 AC: 64720 AN: 151916 Hom.: 18385 Cov.: 32 AF XY: 0.422 AC XY: 31332 AN XY: 74274

African (AFR) AF: 0.820 AC: 34003 AN: 41472

American (AMR) AF: 0.290 AC: 4427 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3468

East Asian (EAS) AF: 0.267 AC: 1378 AN: 5166

South Asian (SAS) AF: 0.255 AC: 1225 AN: 4810

European-Finnish (FIN) AF: 0.311 AC: 3277 AN: 10546

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18504 AN: 67898

Other (OTH) AF: 0.361 AC: 760 AN: 2104

Alfa AF: 0.296 Hom.: 9394

Bravo AF: 0.441

Asia WGS AF: 0.327 AC: 1135 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.30
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3732136; hg19: chr2-58387000; COSMIC: COSV52078210; COSMIC: COSV52078210;