21-46215262-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002340.6(LSS):c.929A>G(p.His310Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,609,986 control chromosomes in the GnomAD database, including 20,718 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1609 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19109 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0240

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022788644).

BP6

Variant 21-46215262-T-C is Benign according to our data. Variant chr21-46215262-T-C is described in ClinVar as [Benign]. Clinvar id is 677221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LSS	NM_002340.6 link	c.929A>G	p.His310Arg	missense_variant	Exon 9 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 link	c.929A>G	p.His310Arg	missense_variant	Exon 9 of 23		NP_001001438.1
LSS	NM_001145436.2 link	c.896A>G	p.His299Arg	missense_variant	Exon 9 of 22		NP_001138908.1
LSS	NM_001145437.2 link	c.689A>G	p.His230Arg	missense_variant	Exon 8 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LSS	ENST00000397728.8 link	c.929A>G	p.His310Arg	missense_variant	Exon 9 of 22	1	NM_002340.6	ENSP00000380837.2	P48449-1
LSS	ENST00000356396.8 link	c.929A>G	p.His310Arg	missense_variant	Exon 9 of 23	1		ENSP00000348762.3	P48449-1
LSS	ENST00000457828.6 link	c.689A>G	p.His230Arg	missense_variant	Exon 8 of 21	1		ENSP00000409191.2	P48449-2
LSS	ENST00000522411.5 link	c.896A>G	p.His299Arg	missense_variant	Exon 9 of 22	2		ENSP00000429133.1	P48449-3

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21378

AN:

152054

Hom.:

1607

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.0916

Gnomad SAS

AF:

0.0897

Gnomad FIN

AF:

0.0883

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.157

GnomAD3 exomes

AF:

0.136

AC:

33684

AN:

247726

Hom.:

2449

AF XY:

0.137

AC XY:

18389

AN XY:

134256

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.0958

Gnomad SAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0873

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.158

AC:

230921

AN:

1457814

Hom.:

19109

Cov.:

AF XY:

0.157

AC XY:

113918

AN XY:

725304

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.124

Gnomad4 EAS exome

AF:

0.0843

Gnomad4 SAS exome

AF:

0.104

Gnomad4 FIN exome

AF:

0.0935

Gnomad4 NFE exome

AF:

0.172

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.141

AC:

21395

AN:

152172

Hom.:

1609

Cov.:

AF XY:

0.135

AC XY:

10060

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.120

Gnomad4 EAS

AF:

0.0917

Gnomad4 SAS

AF:

0.0900

Gnomad4 FIN

AF:

0.0883

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.160

Hom.:

2988

Bravo

AF:

0.145

TwinsUK

AF:

0.173

AC:

642

ALSPAC

AF:

0.174

AC:

670

ESP6500AA

AF:

0.126

AC:

556

ESP6500EA

AF:

0.169

AC:

1450

ExAC

AF:

0.136

AC:

16473

Asia WGS

AF:

0.106

AC:

370

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.175

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

LSS-related disorder

Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.3

DANN

Benign

0.38

DEOGEN2

Benign

0.023

T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.52

.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

N;N;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.056

MPC

0.35

ClinPred

0.0029

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over