dbSNP rs2254522: LSS:p.His650His (chr21-46194529-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002340.6(LSS):c.1950T>C(p.His650His) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.66

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 -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 rank	MANE	Protein
LSS	NM_002340.6 link	c.1950T>C	p.His650His	synonymous_variant	Exon 20 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 link	c.1950T>C	p.His650His	synonymous_variant	Exon 20 of 23		NP_001001438.1
LSS	NM_001145436.2 link	c.1917T>C	p.His639His	synonymous_variant	Exon 20 of 22		NP_001138908.1
LSS	NM_001145437.2 link	c.1710T>C	p.His570His	synonymous_variant	Exon 19 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 link	c.1950T>C	p.His650His	synonymous_variant	Exon 20 of 22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38368

AN:

152118

Hom.:

5317

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.219

AC XY:

159331

AN XY:

726916

show subpopulations

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.:

AF XY:

0.257

AC XY:

19139

AN XY:

74426

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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