2-215397898-A-C

Variant names:

• chr2-215397898-A-C
• rs6725958
• NM_212482.4:c.3349-50T>G

Variant summary

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

The NM_212482.4(FN1):​c.3349-50T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,521,204 control chromosomes in the GnomAD database, including 262,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28696 hom., cov: 32)
  • Exomes 𝑓: 0.58 (234300 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.418
• Publications: 11 publications found

Genes affected

FN1 (HGNC:3778): (fibronectin 1) This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined. [provided by RefSeq, Jan 2016]

FN1 Gene-Disease associations (from GenCC):

• spondylometaphyseal dysplasia, 'corner fracture' type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, ClinGen
• glomerulopathy with fibronectin deposits 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• fibronectin glomerulopathy

  Inheritance: AD 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=-0.82).
• BP6: Variant 2-215397898-A-C is Benign according to our data. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215397898-A-C is described in CliVar as Benign. Clinvar id is 1227605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.3349-50T>G		intron_variant	Intron 21 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.3349-50T>G		intron_variant	Intron 21 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92648 AN: 151964 Hom.: 28695 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.606

GnomAD2 exomes AF: 0.608 AC: 151758 AN: 249656 AF XY: 0.596

Gnomad AFR exome AF: 0.656

Gnomad AMR exome AF: 0.689

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.931

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.580 AC: 794673 AN: 1369122 Hom.: 234300 Cov.: 21 AF XY: 0.576 AC XY: 395013 AN XY: 686348

African (AFR) AF: 0.647 AC: 20429 AN: 31562

American (AMR) AF: 0.687 AC: 30577 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 15238 AN: 25562

East Asian (EAS) AF: 0.946 AC: 37137 AN: 39248

South Asian (SAS) AF: 0.473 AC: 39898 AN: 84342

European-Finnish (FIN) AF: 0.598 AC: 31779 AN: 53174

Middle Eastern (MID) AF: 0.618 AC: 3434 AN: 5558

European-Non Finnish (NFE) AF: 0.567 AC: 582266 AN: 1027812

Other (OTH) AF: 0.591 AC: 33915 AN: 57352

GnomAD4 genome AF: 0.609 AC: 92678 AN: 152082 Hom.: 28696 Cov.: 32 AF XY: 0.613 AC XY: 45536 AN XY: 74342

African (AFR) AF: 0.650 AC: 26960 AN: 41472

American (AMR) AF: 0.657 AC: 10042 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2100 AN: 3466

East Asian (EAS) AF: 0.932 AC: 4820 AN: 5172

South Asian (SAS) AF: 0.476 AC: 2294 AN: 4822

European-Finnish (FIN) AF: 0.608 AC: 6430 AN: 10578

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 38021 AN: 67980

Other (OTH) AF: 0.610 AC: 1287 AN: 2110

Alfa AF: 0.539 Hom.: 3510

Bravo AF: 0.622

Asia WGS AF: 0.676 AC: 2355 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.83
DANN	Benign	0.62
PhyloP100		-0.42
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: rs6725958; hg19: chr2-216262621;