2-215361919-A-C

Variant names:

• chr2-215361919-A-C
• rs13394662
• NM_212482.4:c.7362+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.7362+50T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,598,568 control chromosomes in the GnomAD database, including 104,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7895 hom., cov: 32)
  • Exomes 𝑓: 0.35 (96919 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0170

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]

ATIC (HGNC:794): (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-215361919-A-C is Benign according to our data. Variant chr2-215361919-A-C is described in ClinVar as [Benign]. Clinvar id is 1222395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.7362+50T>G		intron_variant	Intron 45 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.7362+50T>G		intron_variant	Intron 45 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46073 AN: 151878 Hom.: 7890 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.307

GnomAD2 exomes AF: 0.294 AC: 72132 AN: 245560 AF XY: 0.294

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.000992

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.352 AC: 509809 AN: 1446572 Hom.: 96919 Cov.: 29 AF XY: 0.347 AC XY: 249674 AN XY: 719838

African (AFR) AF: 0.190 AC: 6336 AN: 33290

American (AMR) AF: 0.211 AC: 9344 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9658 AN: 25898

East Asian (EAS) AF: 0.00177 AC: 70 AN: 39644

South Asian (SAS) AF: 0.153 AC: 13120 AN: 85526

European-Finnish (FIN) AF: 0.443 AC: 23523 AN: 53058

Middle Eastern (MID) AF: 0.302 AC: 1549 AN: 5134

European-Non Finnish (NFE) AF: 0.388 AC: 426782 AN: 1099816

Other (OTH) AF: 0.324 AC: 19427 AN: 59880

GnomAD4 genome AF: 0.303 AC: 46095 AN: 151996 Hom.: 7895 Cov.: 32 AF XY: 0.301 AC XY: 22391 AN XY: 74288

African (AFR) AF: 0.193 AC: 8015 AN: 41490

American (AMR) AF: 0.263 AC: 4009 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3468

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5178

South Asian (SAS) AF: 0.133 AC: 643 AN: 4818

European-Finnish (FIN) AF: 0.456 AC: 4806 AN: 10532

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26207 AN: 67934

Other (OTH) AF: 0.303 AC: 639 AN: 2108

Alfa AF: 0.355 Hom.: 1904

Bravo AF: 0.286

Asia WGS AF: 0.0740 AC: 259 AN: 3478

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

- -

Nov 11, 2018

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	-0.81
CADD	Benign	3.1
DANN	Benign	0.56
PhyloP100		-0.017
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

Publications

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Other links and lift over

dbSNP: rs13394662; hg19: chr2-216226642; COSMIC: COSV60552112; COSMIC: COSV60552112;