21-46191135-T-C

Variant names:

• chr21-46191135-T-C
• NM_002340.6:c.2168A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002340.6(LSS):​c.2168A>G​(p.Tyr723Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.2168A>G	p.Tyr723Cys	missense_variant	Exon 22 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.2168A>G	p.Tyr723Cys	missense_variant	Exon 22 of 23		NP_001001438.1
LSS	NM_001145436.2	c.2135A>G	p.Tyr712Cys	missense_variant	Exon 22 of 22		NP_001138908.1
LSS	NM_001145437.2	c.1928A>G	p.Tyr643Cys	missense_variant	Exon 21 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.2168A>G	p.Tyr723Cys	missense_variant	Exon 22 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0088	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.1	M;M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.044	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.50
MutPred		0.49		Loss of disorder (P = 0.0853);Loss of disorder (P = 0.0853);.;.;
MVP		0.67
MPC		1.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47611049;