2-58161561-A-G

Variant names:

• chr2-58161561-A-G
• rs848291
• NM_018062.4:c.981T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018062.4(FANCL):​c.981T>C​(p.Ser327Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,608,860 control chromosomes in the GnomAD database, including 321,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37646 hom., cov: 32)
  • Exomes 𝑓: 0.62 (283716 hom.)
• Consequence: FANCL NM_018062.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.551
• Publications: 38 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-58161561-A-G is Benign according to our data. Variant chr2-58161561-A-G is described in ClinVar as Benign. ClinVar VariationId is 257495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.551 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018062.4. 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
	FANCL	NM_018062.4	MANE Select	c.981T>C	p.Ser327Ser	synonymous	Exon 12 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.1026T>C	p.Ser342Ser	synonymous	Exon 13 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.1041T>C	p.Ser347Ser	synonymous	Exon 13 of 15	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.981T>C	p.Ser327Ser	synonymous	Exon 12 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.897T>C	p.Ser299Ser	synonymous	Exon 11 of 13	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.804T>C	p.Ser268Ser	synonymous	Exon 9 of 11	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes AF: 0.692 AC: 104904 AN: 151584 Hom.: 37585 Cov.: 32

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.643 AC: 161260 AN: 250620 AF XY: 0.638

Gnomad AFR exome AF: 0.909

Gnomad AMR exome AF: 0.680

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.609

Gnomad OTH exome AF: 0.623

GnomAD4 exome AF: 0.621 AC: 905009 AN: 1457158 Hom.: 283716 Cov.: 35 AF XY: 0.621 AC XY: 450648 AN XY: 725104

African (AFR) AF: 0.916 AC: 30556 AN: 33376

American (AMR) AF: 0.673 AC: 30057 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 14236 AN: 26034

East Asian (EAS) AF: 0.571 AC: 22595 AN: 39556

South Asian (SAS) AF: 0.663 AC: 57151 AN: 86152

European-Finnish (FIN) AF: 0.653 AC: 34863 AN: 53388

Middle Eastern (MID) AF: 0.557 AC: 3207 AN: 5758

European-Non Finnish (NFE) AF: 0.608 AC: 674117 AN: 1108018

Other (OTH) AF: 0.635 AC: 38227 AN: 60224

GnomAD4 genome AF: 0.692 AC: 105025 AN: 151702 Hom.: 37646 Cov.: 32 AF XY: 0.693 AC XY: 51339 AN XY: 74130

African (AFR) AF: 0.898 AC: 37237 AN: 41476

American (AMR) AF: 0.645 AC: 9808 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1874 AN: 3462

East Asian (EAS) AF: 0.575 AC: 2967 AN: 5160

South Asian (SAS) AF: 0.670 AC: 3227 AN: 4818

European-Finnish (FIN) AF: 0.637 AC: 6718 AN: 10540

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.608 AC: 41183 AN: 67734

Other (OTH) AF: 0.656 AC: 1378 AN: 2102

Alfa AF: 0.631 Hom.: 139602

Bravo AF: 0.700

Asia WGS AF: 0.681 AC: 2364 AN: 3476

EpiCase AF: 0.609

EpiControl AF: 0.597

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group L (5)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.2
DANN	Benign	0.74
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs848291; hg19: chr2-58388696; COSMIC: COSV52073421; COSMIC: COSV52073421;