rs188858500

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_003240.5(LEFTY2):c.474C>T(p.Asn158Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.0012 in 1,583,616 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 39 hom. )

Consequence

LEFTY2
NM_003240.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.53

Publications

4 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 1-225939779-G-A is Benign according to our data. Variant chr1-225939779-G-A is described in ClinVar as Benign. ClinVar VariationId is 259008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00127 (194/152366) while in subpopulation EAS AF = 0.0354 (183/5176). AF 95% confidence interval is 0.0312. There are 6 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEFTY2	NM_003240.5 link	c.474C>T	p.Asn158Asn	synonymous_variant	Exon 2 of 4	ENST00000366820.10	NP_003231.2	O00292-1A1NY82
LEFTY2	NM_001172425.3 link	c.372C>T	p.Asn124Asn	synonymous_variant	Exon 3 of 5		NP_001165896.1	O00292-2
LEFTY2	XM_011544266.2 link	c.474C>T	p.Asn158Asn	synonymous_variant	Exon 2 of 4		XP_011542568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LEFTY2	ENST00000366820.10 link	c.474C>T	p.Asn158Asn	synonymous_variant	Exon 2 of 4	1	NM_003240.5	ENSP00000355785.5	O00292-1
LEFTY2	ENST00000420304.6 link	c.372C>T	p.Asn124Asn	synonymous_variant	Exon 3 of 5	2		ENSP00000388009.2	O00292-2
LEFTY2	ENST00000474493.1 link	n.323C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0355

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00314

AC:

585

AN:

186210

AF XY:

0.00284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000229

Gnomad EAS exome

AF:

0.0370

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000515

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00119

AC:

1705

AN:

1431250

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

833

AN XY:

710132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33064

American (AMR)

AF:

0.00

AC:

AN:

39946

Ashkenazi Jewish (ASJ)

AF:

0.000117

AC:

AN:

25594

East Asian (EAS)

AF:

0.0398

AC:

1540

AN:

38682

South Asian (SAS)

AF:

0.000893

AC:

AN:

83972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46098

Middle Eastern (MID)

AF:

0.00120

AC:

AN:

4162

European-Non Finnish (NFE)

AF:

0.0000209

AC:

AN:

1100556

Other (OTH)

AF:

0.000997

AC:

AN:

59176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

102

204

307

409

511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00127

AC:

194

AN:

152366

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0354

AC:

183

AN:

5176

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000283

Hom.:

Bravo

AF:

0.00173

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Left-right axis malformations

Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: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

-0.40

CADD

Benign

9.7

(source)

DANN

Uncertain

0.98

PhyloP100

4.5

Mutation Taster

=100/0

polymorphism

(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