rs2254524

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_002340.6(LSS):c.1924T>G(p.Leu642Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 1,613,400 control chromosomes in the GnomAD database, including 358,164 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 40195 hom., cov: 35)

Exomes 𝑓: 0.66 ( 317969 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.50

Publications

61 publications found

Variant links:

Genes affected

LSS (HGNC:6708): (lanosterol synthase) The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

LSS Gene-Disease associations (from GenCC):

alopecia-intellectual disability syndrome 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 44
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypotrichosis 14
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
hypotrichosis simplex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive palmoplantar keratoderma and congenital alopecia
Inheritance: AR Classification: LIMITED Submitted by: G2P

LSS 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 (MetaRNN=6.926981E-7).

BP6

Variant 21-46194555-A-C is Benign according to our data. Variant chr21-46194555-A-C is described in ClinVar as Benign. ClinVar VariationId is 677175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LSS	NM_002340.6 link	c.1924T>G	p.Leu642Val	missense_variant	Exon 20 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 link	c.1924T>G	p.Leu642Val	missense_variant	Exon 20 of 23		NP_001001438.1
LSS	NM_001145436.2 link	c.1891T>G	p.Leu631Val	missense_variant	Exon 20 of 22		NP_001138908.1
LSS	NM_001145437.2 link	c.1684T>G	p.Leu562Val	missense_variant	Exon 19 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 link	c.1924T>G	p.Leu642Val	missense_variant	Exon 20 of 22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.718

AC:

109236

AN:

152108

Hom.:

40138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.795

Gnomad AMR

AF:

0.604

Gnomad ASJ

AF:

0.740

Gnomad EAS

AF:

0.695

Gnomad SAS

AF:

0.677

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.657

Gnomad OTH

AF:

0.718

GnomAD2 exomes

AF:

0.661

AC:

165419

AN:

250214

AF XY:

0.664

show subpopulations

Gnomad AFR exome

AF:

0.891

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.727

Gnomad EAS exome

AF:

0.696

Gnomad FIN exome

AF:

0.641

Gnomad NFE exome

AF:

0.661

Gnomad OTH exome

AF:

0.665

GnomAD4 exome

AF:

0.657

AC:

960592

AN:

1461174

Hom.:

317969

Cov.:

AF XY:

0.659

AC XY:

479251

AN XY:

726894

show subpopulations

African (AFR)

AF:

0.900

AC:

30126

AN:

33478

American (AMR)

AF:

0.525

AC:

23470

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.730

AC:

19085

AN:

26128

East Asian (EAS)

AF:

0.742

AC:

29461

AN:

39686

South Asian (SAS)

AF:

0.680

AC:

58644

AN:

86244

European-Finnish (FIN)

AF:

0.641

AC:

33981

AN:

53004

Middle Eastern (MID)

AF:

0.733

AC:

4226

AN:

5764

European-Non Finnish (NFE)

AF:

0.648

AC:

720862

AN:

1111798

Other (OTH)

AF:

0.675

AC:

40737

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18911

37823

56734

75646

94557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18994

37988

56982

75976

94970

<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:

0.718

AC:

109346

AN:

152226

Hom.:

40195

Cov.:

AF XY:

0.714

AC XY:

53121

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.886

AC:

36844

AN:

41568

American (AMR)

AF:

0.604

AC:

9241

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.740

AC:

2567

AN:

3470

East Asian (EAS)

AF:

0.696

AC:

3592

AN:

5164

South Asian (SAS)

AF:

0.677

AC:

3268

AN:

4828

European-Finnish (FIN)

AF:

0.637

AC:

6751

AN:

10592

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.656

AC:

44630

AN:

67982

Other (OTH)

AF:

0.719

AC:

1521

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1588

3176

4763

6351

7939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.678

Hom.:

119706

Bravo

AF:

0.724

TwinsUK

AF:

0.643

AC:

2385

ALSPAC

AF:

0.640

AC:

2465

ESP6500AA

AF:

0.889

AC:

3915

ESP6500EA

AF:

0.667

AC:

5732

ExAC

AF:

0.673

AC:

81769

Asia WGS

AF:

0.710

AC:

2469

AN:

3478

EpiCase

AF:

0.662

EpiControl

AF:

0.674

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 24, 2018

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cataract 44

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alopecia-intellectual disability syndrome 4

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.6

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.024

T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.11

.;T;T;T

MetaRNN

Benign

6.9e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.8

N;N;.;.

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

2.3

N;N;N;N

REVEL

Benign

0.031

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.034

MPC

0.29

ClinPred

0.00060

GERP RS

3.3

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.22

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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