rs2254524

chr21-46194555-A-CchrNT_187626.1-55924-A-Cchr21-46194555-A-TchrNT_187626.1-55924-A-Tchr21-46194555-A-GchrNT_187626.1-55924-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
LSS	NM_002340.6	c.1924T>G	p.Leu642Val	missense_variant	20/22	ENST00000397728.8
LSS	NM_001001438.3	c.1924T>G	p.Leu642Val	missense_variant	20/23
LSS	NM_001145436.2	c.1891T>G	p.Leu631Val	missense_variant	20/22
LSS	NM_001145437.2	c.1684T>G	p.Leu562Val	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.1924T>G	p.Leu642Val	missense_variant	20/22	1	NM_002340.6	P1

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109236 AN: 152108 Hom.: 40138 Cov.: 35

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

GnomAD3 exomes AF: 0.661 AC: 165419 AN: 250214 Hom.: 55713 AF XY: 0.664 AC XY: 89891 AN XY: 135438

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 SAS exome AF: 0.679

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.: 58 AF XY: 0.659 AC XY: 479251 AN XY: 726894

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.730

Gnomad4 EAS exome AF: 0.742

Gnomad4 SAS exome AF: 0.680

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.718 AC: 109346 AN: 152226 Hom.: 40195 Cov.: 35 AF XY: 0.714 AC XY: 53121 AN XY: 74424

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.604

Gnomad4 ASJ AF: 0.740

Gnomad4 EAS AF: 0.696

Gnomad4 SAS AF: 0.677

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.719

Alfa AF: 0.668 Hom.: 83423

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cataract 44 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Alopecia-intellectual disability syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.6
Dann	Benign	0.70
DEOGEN2	Benign	0.024	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	6.9e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.8	N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.46	T
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	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs2254524; hg19: chr21-47614469; COSMIC: COSV62701085; COSMIC: COSV62701085;