rs2839158

chr21-46221880-C-Tchr21-46221880-C-A

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.524G>A(p.Arg175Gln) variant causes a missense change. The variant allele was found at a frequency of 0.156 in 1,613,904 control chromosomes in the GnomAD database, including 20,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1640 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18942 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.98

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020841062).
• BP6: Variant 21-46221880-C-T is Benign according to our data. Variant chr21-46221880-C-T is described in ClinVar as [Benign]. Clinvar id is 677220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.524G>A	p.Arg175Gln	missense_variant	5/22	ENST00000397728.8
LSS	NM_001001438.3	c.524G>A	p.Arg175Gln	missense_variant	5/23
LSS	NM_001145436.2	c.491G>A	p.Arg164Gln	missense_variant	5/22
LSS	NM_001145437.2	c.284G>A	p.Arg95Gln	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.524G>A	p.Arg175Gln	missense_variant	5/22	1	NM_002340.6	P1
	ENST00000626933.1	n.252C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21766 AN: 151964 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.136 AC: 34159 AN: 251468 Hom.: 2475 AF XY: 0.137 AC XY: 18568 AN XY: 135906

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.0956

Gnomad SAS exome AF: 0.0999

Gnomad FIN exome AF: 0.0888

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 230576 AN: 1461822 Hom.: 18942 Cov.: 34 AF XY: 0.156 AC XY: 113725 AN XY: 727208

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.0838

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0946

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152082 Hom.: 1640 Cov.: 32 AF XY: 0.137 AC XY: 10211 AN XY: 74348

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.0909

Gnomad4 SAS AF: 0.0886

Gnomad4 FIN AF: 0.0875

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.155

Alfa AF: 0.160 Hom.: 5161

Bravo AF: 0.149

TwinsUK AF: 0.173 AC: 641

ALSPAC AF: 0.174 AC: 669

ESP6500AA AF: 0.135 AC: 597

ESP6500EA AF: 0.168 AC: 1444

ExAC AF: 0.136 AC: 16564

Asia WGS AF: 0.105 AC: 368 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	- -

LSS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

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	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
MutationTaster	Benign	8.7e-9	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.055	T;T;D;T;D
Sift4G	Benign	0.092	T;T;T;T;T
Polyphen		0.62	P;P;.;.;.
Vest4		0.23
MPC		0.47
ClinPred		0.030	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.71

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

Other links and lift over

dbSNP: rs2839158; hg19: chr21-47641794; COSMIC: COSV62699775;