chr2-58160123-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018062.4(FANCL):c.1077T>C(p.Cys359Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,612,658 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 305 hom. )

Consequence

FANCL
NM_018062.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.49

Publications

6 publications found

Variant links:

COSMIC-nc: COSV52073891

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]

FANCL links:

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]

VRK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-58160123-A-G is Benign according to our data. Variant chr2-58160123-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2069/152184) while in subpopulation NFE AF = 0.0209 (1419/67924). AF 95% confidence interval is 0.02. There are 24 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.1077T>C	p.Cys359Cys	synonymous_variant	Exon 13 of 14	ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9 link	c.1077T>C	p.Cys359Cys	synonymous_variant	Exon 13 of 14	1	NM_018062.4	ENSP00000233741.5		Q9NW38-1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2067

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00434

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0135

AC:

3374

AN:

250798

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00862

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00878

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0186

AC:

27213

AN:

1460474

Hom.:

305

Cov.:

AF XY:

0.0182

AC XY:

13232

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.00356

AC:

119

AN:

33446

American (AMR)

AF:

0.00917

AC:

410

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

389

AN:

26088

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39564

South Asian (SAS)

AF:

0.00799

AC:

689

AN:

86234

European-Finnish (FIN)

AF:

0.00959

AC:

512

AN:

53412

Middle Eastern (MID)

AF:

0.0278

AC:

160

AN:

5750

European-Non Finnish (NFE)

AF:

0.0216

AC:

23941

AN:

1110932

Other (OTH)

AF:

0.0164

AC:

991

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1256

2512

3768

5024

6280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

894

1788

2682

3576

4470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0136

AC:

2069

AN:

152184

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

965

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41566

American (AMR)

AF:

0.0138

AC:

210

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00932

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0107

AC:

114

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0209

AC:

1419

AN:

67924

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0187

Hom.:

Bravo

AF:

0.0132

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fanconi anemia complementation group L

Benign:2

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Fanconi anemia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.48

CADD

Benign

6.1

(source)

DANN

Benign

0.79

PhyloP100

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over