Variant 21-46191924-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002340.6(LSS):c.2024G>A(p.Arg675Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.278

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:

LSS (HGNC:):

LSS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10215241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LSS	NM_002340.6 linkuse as main transcript	c.2024G>A	p.Arg675Gln	missense_variant	21/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 linkuse as main transcript	c.2024G>A	p.Arg675Gln	missense_variant	21/23		NP_001001438.1
LSS	NM_001145436.2 linkuse as main transcript	c.1991G>A	p.Arg664Gln	missense_variant	21/22		NP_001138908.1
LSS	NM_001145437.2 linkuse as main transcript	c.1784G>A	p.Arg595Gln	missense_variant	20/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 linkuse as main transcript	c.2024G>A	p.Arg675Gln	missense_variant	21/22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000680

AC:

AN:

249924

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461416

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.2024G>A (p.R675Q) alteration is located in exon 21 (coding exon 21) of the LSS gene. This alteration results from a G to A substitution at nucleotide position 2024, causing the arginine (R) at amino acid position 675 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.9

DANN

Benign

0.97

DEOGEN2

Benign

0.042

T;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.81

.;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;N;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.32

N;N;N;N

REVEL

Benign

0.015

Sift

Benign

0.31

T;T;T;T

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.0080

B;B;.;.

Vest4

0.092

MVP

0.26

MPC

0.33

ClinPred

0.027

GERP RS

0.74

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.039

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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