rs2254522

chr21-46194529-A-GchrNT_187626.1-55898-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002340.6(LSS):c.1950T>C(p.His650=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,500 control chromosomes in the GnomAD database, including 44,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5320 hom., cov: 35)
  • Exomes 𝑓: 0.22 (39026 hom.)
• Consequence: LSS NM_002340.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 21-46194529-A-G is Benign according to our data. Variant chr21-46194529-A-G is described in ClinVar as [Benign]. Clinvar id is 677176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.1950T>C	p.His650=	synonymous_variant	20/22	ENST00000397728.8
LSS	NM_001001438.3	c.1950T>C	p.His650=	synonymous_variant	20/23
LSS	NM_001145436.2	c.1917T>C	p.His639=	synonymous_variant	20/22
LSS	NM_001145437.2	c.1710T>C	p.His570=	synonymous_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.1950T>C	p.His650=	synonymous_variant	20/22	1	NM_002340.6	P1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38368 AN: 152118 Hom.: 5317 Cov.: 35

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.257 AC: 64412 AN: 250270 Hom.: 9580 AF XY: 0.258 AC XY: 34941 AN XY: 135446

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.569

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.215 AC: 314667 AN: 1461264 Hom.: 39026 Cov.: 36 AF XY: 0.219 AC XY: 159331 AN XY: 726916

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.252 AC: 38382 AN: 152236 Hom.: 5320 Cov.: 35 AF XY: 0.257 AC XY: 19139 AN XY: 74426

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.569

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.249

Alfa AF: 0.213 Hom.: 4670

Bravo AF: 0.258

Asia WGS AF: 0.390 AC: 1355 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.209

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.9
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2254522; hg19: chr21-47614443; COSMIC: COSV62700896; COSMIC: COSV62700896;