21-46191134-GT-CG

Variant names:

• chr21-46191134-GT-CG
• NM_002340.6:c.2168_2169delACinsCG
• LSS p.Tyr723Ser

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002340.6(LSS):​c.2168_2169delACinsCG​(p.Tyr723Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.2168_2169delACinsCG	p.Tyr723Ser	missense	N/A	NP_002331.3
	LSS	NM_001001438.3		c.2168_2169delACinsCG	p.Tyr723Ser	missense	N/A	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.2135_2136delACinsCG	p.Tyr712Ser	missense	N/A	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.2168_2169delACinsCG	p.Tyr723Ser	missense	N/A	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.2168_2169delACinsCG	p.Tyr723Ser	missense	N/A	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.1928_1929delACinsCG	p.Tyr643Ser	missense	N/A	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-47611048;