chr21-46188666-G-A

Variant names:

• chr21-46188666-G-A
• rs2968
• NM_002340.6:c.*2438C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002340.6(LSS):​c.*2438C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 470,372 control chromosomes in the GnomAD database, including 79,362 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (24748 hom., cov: 29)
  • Exomes 𝑓: 0.58 (54614 hom.)
• Consequence: LSS NM_002340.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.686
• Publications: 40 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

ENSG00000228404 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 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.*2438C>T		3_prime_UTR	Exon 22 of 22	NP_002331.3
	LSS	NM_001001438.3		c.*194C>T		3_prime_UTR	Exon 23 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.*2438C>T		3_prime_UTR	Exon 22 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.*2438C>T		3_prime_UTR	Exon 22 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.*194C>T		3_prime_UTR	Exon 23 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000419093.5	TSL:3	c.324C>T	p.His108His	synonymous	Exon 3 of 3	ENSP00000410678.1	H7C3A5

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86278 AN: 151502 Hom.: 24745 Cov.: 29

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.576 AC: 87443 AN: 151736 AF XY: 0.583

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.684

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.583 AC: 185698 AN: 318754 Hom.: 54614 Cov.: 0 AF XY: 0.587 AC XY: 105730 AN XY: 180066

African (AFR) AF: 0.525 AC: 4532 AN: 8632

American (AMR) AF: 0.471 AC: 12855 AN: 27280

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 7326 AN: 10788

East Asian (EAS) AF: 0.693 AC: 6384 AN: 9214

South Asian (SAS) AF: 0.593 AC: 35430 AN: 59742

European-Finnish (FIN) AF: 0.567 AC: 15289 AN: 26948

Middle Eastern (MID) AF: 0.696 AC: 1938 AN: 2784

European-Non Finnish (NFE) AF: 0.587 AC: 93284 AN: 159036

Other (OTH) AF: 0.604 AC: 8660 AN: 14330

GnomAD4 genome AF: 0.569 AC: 86311 AN: 151618 Hom.: 24748 Cov.: 29 AF XY: 0.569 AC XY: 42127 AN XY: 74096

African (AFR) AF: 0.529 AC: 21827 AN: 41278

American (AMR) AF: 0.528 AC: 8056 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2380 AN: 3466

East Asian (EAS) AF: 0.689 AC: 3540 AN: 5140

South Asian (SAS) AF: 0.580 AC: 2762 AN: 4758

European-Finnish (FIN) AF: 0.572 AC: 6014 AN: 10510

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39670 AN: 67908

Other (OTH) AF: 0.589 AC: 1239 AN: 2104

Alfa AF: 0.578 Hom.: 44710

Bravo AF: 0.566

Asia WGS AF: 0.595 AC: 2070 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2968; hg19: chr21-47608580; COSMIC: COSV52433261; COSMIC: COSV52433261;