dbSNP rs28763953: FBN2:c.1231+37C>G (chr5-128395085-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):c.1231+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 1,611,942 control chromosomes in the GnomAD database, including 1,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 94 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1570 hom. )

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.25

Variant links:

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]

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 5-128395085-G-C is Benign according to our data. Variant chr5-128395085-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 258507.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 = 0.0305 (4641/152284) while in subpopulation NFE AF= 0.0439 (2984/68010). AF 95% confidence interval is 0.0426. There are 94 homozygotes in gnomad4. There are 2152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4641 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.1231+37C>G		intron_variant	Intron 9 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.1079-1717C>G		intron_variant	Intron 8 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.1231+37C>G	intron_variant	Intron 9 of 64	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000508989.5 link	c.1132+37C>G	intron_variant	Intron 8 of 32	2		ENSP00000425596.1	D6RJI3
FBN2	ENST00000703787.1 link	n.938+37C>G	intron_variant	Intron 8 of 9

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4640

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00878

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0390

Gnomad ASJ

AF:

0.0605

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0275

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0350

AC:

8772

AN:

250556

Hom.:

205

AF XY:

0.0341

AC XY:

4612

AN XY:

135426

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.0655

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0341

Gnomad NFE exome

AF:

0.0418

Gnomad OTH exome

AF:

0.0359

GnomAD4 exome

AF:

0.0439

AC:

64059

AN:

1459658

Hom.:

1570

Cov.:

AF XY:

0.0431

AC XY:

31300

AN XY:

726244

show subpopulations

Gnomad4 AFR exome

AF:

0.00694

Gnomad4 AMR exome

AF:

0.0454

Gnomad4 ASJ exome

AF:

0.0644

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0232

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0484

Gnomad4 OTH exome

AF:

0.0415

GnomAD4 genome

AF:

0.0305

AC:

4641

AN:

152284

Hom.:

Cov.:

AF XY:

0.0289

AC XY:

2152

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00876

Gnomad4 AMR

AF:

0.0391

Gnomad4 ASJ

AF:

0.0605

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0211

Gnomad4 FIN

AF:

0.0275

Gnomad4 NFE

AF:

0.0439

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0407

Hom.:

Bravo

AF:

0.0306

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely 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

-0.87

CADD

Benign

0.078

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over