rs2254524

Variant names:

• chr21-46194555-A-C
• rs2254524
• NM_002340.6:c.1924T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46194555-A-C
• chr21-46194555-A-G
• chr21-46194555-A-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5
• Conservation: PhyloP100: 1.50
• Publications: 61 publications found

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 Gene-Disease associations (from GenCC):

• alopecia-intellectual disability syndrome 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 44

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypotrichosis 14

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive palmoplantar keratoderma and congenital alopecia

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002340.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	NM_002340.6	MANE Select	c.1924T>G	p.Leu642Val	missense	Exon 20 of 22	NP_002331.3
	LSS	NM_001001438.3		c.1924T>G	p.Leu642Val	missense	Exon 20 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.1891T>G	p.Leu631Val	missense	Exon 20 of 22	NP_001138908.1	P48449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.1924T>G	p.Leu642Val	missense	Exon 20 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.1924T>G	p.Leu642Val	missense	Exon 20 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.1684T>G	p.Leu562Val	missense	Exon 19 of 21	ENSP00000409191.2	P48449-2

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

GnomAD2 exomes AF: 0.661 AC: 165419 AN: 250214 AF XY: 0.664

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 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

African (AFR) AF: 0.900 AC: 30126 AN: 33478

American (AMR) AF: 0.525 AC: 23470 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 19085 AN: 26128

East Asian (EAS) AF: 0.742 AC: 29461 AN: 39686

South Asian (SAS) AF: 0.680 AC: 58644 AN: 86244

European-Finnish (FIN) AF: 0.641 AC: 33981 AN: 53004

Middle Eastern (MID) AF: 0.733 AC: 4226 AN: 5764

European-Non Finnish (NFE) AF: 0.648 AC: 720862 AN: 1111798

Other (OTH) AF: 0.675 AC: 40737 AN: 60380

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

African (AFR) AF: 0.886 AC: 36844 AN: 41568

American (AMR) AF: 0.604 AC: 9241 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 2567 AN: 3470

East Asian (EAS) AF: 0.696 AC: 3592 AN: 5164

South Asian (SAS) AF: 0.677 AC: 3268 AN: 4828

European-Finnish (FIN) AF: 0.637 AC: 6751 AN: 10592

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44630 AN: 67982

Other (OTH) AF: 0.719 AC: 1521 AN: 2114

Alfa AF: 0.678 Hom.: 119706

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Alopecia-intellectual disability syndrome 4 (1)
-	-	1	Cataract 44 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.8	N
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.29
ClinPred		0.00060	T
GERP RS		3.3
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.22
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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