chr21-46191885-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002340.6(LSS):c.2063C>T(p.Pro688Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,612,632 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts 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 0.013 ( 14 hom., cov: 33)

Exomes 𝑓: 0.018 ( 277 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.54

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=0.009421557).

BP6

Variant 21-46191885-G-A is Benign according to our data. Variant chr21-46191885-G-A is described in ClinVar as [Benign]. Clinvar id is 668540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0127 (1937/152300) while in subpopulation SAS AF= 0.0228 (110/4828). AF 95% confidence interval is 0.0193. There are 14 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LSS	NM_002340.6 link	c.2063C>T	p.Pro688Leu	missense_variant	Exon 21 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 link	c.2063C>T	p.Pro688Leu	missense_variant	Exon 21 of 23		NP_001001438.1
LSS	NM_001145436.2 link	c.2030C>T	p.Pro677Leu	missense_variant	Exon 21 of 22		NP_001138908.1
LSS	NM_001145437.2 link	c.1823C>T	p.Pro608Leu	missense_variant	Exon 20 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 link	c.2063C>T	p.Pro688Leu	missense_variant	Exon 21 of 22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0158

AC:

3920

AN:

247854

Hom.:

AF XY:

0.0174

AC XY:

2334

AN XY:

134254

show subpopulations

Gnomad AFR exome

AF:

0.00260

Gnomad AMR exome

AF:

0.00751

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0259

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0179

AC:

26123

AN:

1460332

Hom.:

277

Cov.:

AF XY:

0.0185

AC XY:

13432

AN XY:

726240

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.00773

Gnomad4 ASJ exome

AF:

0.0130

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0241

Gnomad4 FIN exome

AF:

0.0144

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0159

GnomAD4 genome

AF:

0.0127

AC:

1937

AN:

152300

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

929

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00334

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0228

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0214

AC:

184

ExAC

AF:

0.0161

AC:

1955

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 18, 2020

GeneDx

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

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

.;D;D;D

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.5

D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.51

T;T;D;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.13

MPC

0.95

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.68

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