chr21-46228522-C-T

Position:

chr21-46228522-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002340.6(LSS):c.92G>A(p.Arg31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,601,056 control chromosomes in the GnomAD database, including 10 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 0.0041 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 3 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.158

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047560334).

BP6

Variant 21-46228522-C-T is Benign according to our data. Variant chr21-46228522-C-T is described in ClinVar as [Benign]. Clinvar id is 721064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00414 (631/152324) while in subpopulation AFR AF= 0.0143 (593/41582). AF 95% confidence interval is 0.0133. There are 7 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LSS	NM_002340.6 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant	2/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant	2/23		NP_001001438.1
LSS	NM_001145436.2 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant	2/22		NP_001138908.1
LSS	NM_001145437.2 linkuse as main transcript	c.-149G>A		5_prime_UTR_variant	1/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant	2/22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

631

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.000103

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00107

AC:

239

AN:

223944

Hom.:

AF XY:

0.000778

AC XY:

AN XY:

124668

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.00103

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:

0.00

Gnomad OTH exome

AF:

0.000532

GnomAD4 exome

AF:

0.000414

AC:

600

AN:

1448732

Hom.:

Cov.:

AF XY:

0.000358

AC XY:

258

AN XY:

721110

show subpopulations

Gnomad4 AFR exome

AF:

0.0145

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000649

GnomAD4 genome

AF:

0.00414

AC:

631

AN:

152324

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0143

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000652

Hom.:

Bravo

AF:

0.00483

ESP6500AA

AF:

0.0117

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00132

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LSS: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.72

DANN

Benign

0.94

DEOGEN2

Benign

0.034

T;T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.58

.;T;T;T

MetaRNN

Benign

0.0048

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.65

N;N;N;.

PrimateAI

Benign

0.48

PROVEAN

Benign

0.030

N;N;N;N

REVEL

Benign

0.013

Sift

Benign

0.65

T;T;T;T

Sift4G

Benign

0.85

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.095

MVP

0.20

MPC

0.29

ClinPred

0.011

GERP RS

-8.0

Varity_R

0.073

gMVP

0.35

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