rs28763947

Positions:

• chr5-128350042-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.2813-37C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,523,168 control chromosomes in the GnomAD database, including 862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 33)
  • Exomes 𝑓: 0.032 (800 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-128350042-G-T is Benign according to our data. Variant chr5-128350042-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 258513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3301/152212) while in subpopulation NFE AF= 0.0367 (2495/68012). AF 95% confidence interval is 0.0355. There are 62 homozygotes in gnomad4. There are 1488 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.2813-37C>A		intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.2660-37C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.2813-37C>A		intron_variant		1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.2714-37C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3305 AN: 152094 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00906

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0234 AC: 5868 AN: 250322 Hom.: 105 AF XY: 0.0247 AC XY: 3346 AN XY: 135344

Gnomad AFR exome AF: 0.00613

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0186

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0376

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0324 AC: 44484 AN: 1370956 Hom.: 800 Cov.: 23 AF XY: 0.0320 AC XY: 21996 AN XY: 687358

Gnomad4 AFR exome AF: 0.00492

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0217 AC: 3301 AN: 152212 Hom.: 62 Cov.: 33 AF XY: 0.0200 AC XY: 1488 AN XY: 74416

Gnomad4 AFR AF: 0.00640

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00906

Gnomad4 NFE AF: 0.0367

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0258 Hom.: 11

Bravo AF: 0.0210

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.40

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

LitVar

Other links and lift over

dbSNP: rs28763947; hg19: chr5-127685734;