rs10070365

Variant names:

• chr5-128261826-G-A
• rs10070365
• NM_001999.4:c.8274C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128261826-G-A
• chr5-128261826-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.8274C>T​(p.Ser2758Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,570 control chromosomes in the GnomAD database, including 11,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1447 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9795 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.364
• Publications: 14 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-128261826-G-A is Benign according to our data. Variant chr5-128261826-G-A is described in ClinVar as Benign. ClinVar VariationId is 129053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

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.8274C>T	p.Ser2758Ser	synonymous	Exon 64 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.8274C>T	p.Ser2758Ser	synonymous	Exon 64 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.8175C>T	p.Ser2725Ser	synonymous	Exon 63 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.8121C>T	p.Ser2707Ser	synonymous	Exon 63 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19569 AN: 152020 Hom.: 1448 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0905

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0692

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.102 AC: 25633 AN: 251166 AF XY: 0.100

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.0516

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.112 AC: 163982 AN: 1461432 Hom.: 9795 Cov.: 32 AF XY: 0.111 AC XY: 80521 AN XY: 727054

African (AFR) AF: 0.172 AC: 5754 AN: 33472

American (AMR) AF: 0.0730 AC: 3263 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1443 AN: 26134

East Asian (EAS) AF: 0.0352 AC: 1399 AN: 39696

South Asian (SAS) AF: 0.0644 AC: 5553 AN: 86252

European-Finnish (FIN) AF: 0.137 AC: 7335 AN: 53414

Middle Eastern (MID) AF: 0.0782 AC: 451 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 132496 AN: 1111584

Other (OTH) AF: 0.104 AC: 6288 AN: 60388

GnomAD4 genome AF: 0.129 AC: 19593 AN: 152138 Hom.: 1447 Cov.: 32 AF XY: 0.128 AC XY: 9533 AN XY: 74366

African (AFR) AF: 0.175 AC: 7258 AN: 41492

American (AMR) AF: 0.0904 AC: 1381 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 234 AN: 3472

East Asian (EAS) AF: 0.0404 AC: 209 AN: 5178

South Asian (SAS) AF: 0.0693 AC: 334 AN: 4820

European-Finnish (FIN) AF: 0.146 AC: 1538 AN: 10570

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8263 AN: 68006

Other (OTH) AF: 0.114 AC: 241 AN: 2114

Alfa AF: 0.120 Hom.: 738

Bravo AF: 0.125

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Congenital contractural arachnodactyly (4)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.6
DANN	Benign	0.53
PhyloP100		-0.36
Mutation Taster		=97/3	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: rs10070365; hg19: chr5-127597518; COSMIC: COSV52501113;