2-58159250-T-G

Variant names:

• chr2-58159250-T-G
• rs971589098
• ENST00000449070.6:c.*515A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018062.4(FANCL):​c.*515A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 912,508 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: FANCL NM_018062.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.612
• Publications: 0 publications found

Genes affected

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]

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]

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 (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4	c.*515A>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000233741.9	NP_060532.2
VRK2	NM_006296.7	c.1183-99T>G		intron_variant	Intron 12 of 12	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9	c.*515A>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_018062.4	ENSP00000233741.5
VRK2	ENST00000340157.9	c.1183-99T>G		intron_variant	Intron 12 of 12	1	NM_006296.7	ENSP00000342381.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000276 AC: 21 AN: 760364 Hom.: 0 Cov.: 10 AF XY: 0.0000338 AC XY: 13 AN XY: 384764

African (AFR) AF: 0.00 AC: 0 AN: 18660

American (AMR) AF: 0.00 AC: 0 AN: 22400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15234

East Asian (EAS) AF: 0.00 AC: 0 AN: 35082

South Asian (SAS) AF: 0.00 AC: 0 AN: 41044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2540

European-Non Finnish (NFE) AF: 0.0000349 AC: 19 AN: 545066

Other (OTH) AF: 0.0000563 AC: 2 AN: 35548

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group L Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.59
PhyloP100		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs971589098; hg19: chr2-58386385;