rs78727187

Variant names:

• chr5-128332993-G-T
• rs78727187
• NM_001999.4:c.4141C>A
• FBN2 p.His1381Asn

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):​c.4141C>A​(p.His1381Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00512 in 1,608,724 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H1381H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (23 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 5.62
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_001999.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.012713194).
• BP6: Variant 5-128332993-G-T is Benign according to our data. Variant chr5-128332993-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210996.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00323 (492/152278) while in subpopulation NFE AF = 0.00529 (360/68032). AF 95% confidence interval is 0.00484. There are 1 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 492 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. 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
	FBN2	NM_001999.4	MANE Select	c.4141C>A	p.His1381Asn	missense	Exon 32 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.4141C>A	p.His1381Asn	missense	Exon 32 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.4042C>A	p.His1348Asn	missense	Exon 31 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.3988C>A	p.His1330Asn	missense	Exon 31 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00372 AC: 934 AN: 251292 AF XY: 0.00360

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.00576

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00531 AC: 7739 AN: 1456446 Hom.: 23 Cov.: 29 AF XY: 0.00511 AC XY: 3702 AN XY: 724838

African (AFR) AF: 0.000689 AC: 23 AN: 33364

American (AMR) AF: 0.00177 AC: 79 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00656 AC: 171 AN: 26086

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.00169 AC: 146 AN: 86152

European-Finnish (FIN) AF: 0.00386 AC: 206 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.00622 AC: 6890 AN: 1107078

Other (OTH) AF: 0.00352 AC: 212 AN: 60214

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74464

African (AFR) AF: 0.00101 AC: 42 AN: 41552

American (AMR) AF: 0.00131 AC: 20 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00529 AC: 360 AN: 68032

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00497 Hom.: 15

Bravo AF: 0.00305

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00456

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not specified (7)
-	-	4	not provided (4)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	Connective tissue disorder (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.054
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-1.5	N
PhyloP100		5.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.55
Sift	Benign	0.29	T
Sift4G	Benign	1.0	T
Varity_R		0.29
gMVP		0.65
Mutation Taster		=31/69	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78727187;

hg19: chr5-127668685;

COSMIC: COSV99075149;