rs74578461

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003240.5(LEFTY2):c.497+13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,597,580 control chromosomes in the GnomAD database, including 76,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8009 hom., cov: 34)

Exomes 𝑓: 0.31 ( 68855 hom. )

Consequence

LEFTY2
NM_003240.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.70

Publications

8 publications found

Variant links:

Genes affected

LEFTY2 (HGNC:3122): (left-right determination factor 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

LEFTY2 Gene-Disease associations (from GenCC):

visceral heterotaxy
Inheritance: AD Classification: LIMITED Submitted by: G2P
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LEFTY2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-225939743-G-C is Benign according to our data. Variant chr1-225939743-G-C is described in ClinVar as Benign. ClinVar VariationId is 138108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LEFTY2	NM_003240.5 link	c.497+13C>G	intron_variant	Intron 2 of 3	ENST00000366820.10	NP_003231.2	O00292-1A1NY82
LEFTY2	NM_001172425.3 link	c.395+13C>G	intron_variant	Intron 3 of 4		NP_001165896.1	O00292-2
LEFTY2	XM_011544266.2 link	c.497+13C>G	intron_variant	Intron 2 of 3		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LEFTY2	ENST00000366820.10 link	c.497+13C>G	intron_variant	Intron 2 of 3	1	NM_003240.5	ENSP00000355785.5	O00292-1
LEFTY2	ENST00000420304.6 link	c.395+13C>G	intron_variant	Intron 3 of 4	2		ENSP00000388009.2	O00292-2
LEFTY2	ENST00000474493.1 link	n.346+13C>G	intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

49063

AN:

151748

Hom.:

8009

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.375

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.337

GnomAD2 exomes

AF:

0.311

AC:

65247

AN:

210088

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.362

Gnomad AMR exome

AF:

0.420

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.143

Gnomad FIN exome

AF:

0.326

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.307

AC:

443228

AN:

1445714

Hom.:

68855

Cov.:

AF XY:

0.303

AC XY:

218021

AN XY:

718570

show subpopulations

African (AFR)

AF:

0.353

AC:

11660

AN:

33076

American (AMR)

AF:

0.412

AC:

17449

AN:

42326

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

8288

AN:

25832

East Asian (EAS)

AF:

0.156

AC:

6133

AN:

39342

South Asian (SAS)

AF:

0.235

AC:

20089

AN:

85486

European-Finnish (FIN)

AF:

0.317

AC:

15623

AN:

49276

Middle Eastern (MID)

AF:

0.383

AC:

1687

AN:

4410

European-Non Finnish (NFE)

AF:

0.311

AC:

344153

AN:

1106350

Other (OTH)

AF:

0.304

AC:

18146

AN:

59616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

18178

36356

54534

72712

90890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11370

22740

34110

45480

56850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.323

AC:

49094

AN:

151866

Hom.:

8009

Cov.:

AF XY:

0.322

AC XY:

23932

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.357

AC:

14713

AN:

41258

American (AMR)

AF:

0.371

AC:

5677

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1123

AN:

3472

East Asian (EAS)

AF:

0.141

AC:

726

AN:

5158

South Asian (SAS)

AF:

0.228

AC:

1101

AN:

4826

European-Finnish (FIN)

AF:

0.337

AC:

3574

AN:

10596

Middle Eastern (MID)

AF:

0.452

AC:

132

AN:

292

European-Non Finnish (NFE)

AF:

0.309

AC:

21000

AN:

67952

Other (OTH)

AF:

0.335

AC:

707

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1715

3430

5144

6859

8574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.320

Hom.:

1411

Bravo

AF:

0.331

Asia WGS

AF:

0.193

AC:

671

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2013

GeneDx

Significance: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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Left-right axis malformations

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.066

(source)

DANN

Benign

0.67

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over