chr21-46191904-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002340.6(LSS):c.2044C>T(p.Leu682Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
LSS
NM_002340.6 missense
NM_002340.6 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 2.98
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.24371973).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LSS | NM_002340.6 | c.2044C>T | p.Leu682Phe | missense_variant | 21/22 | ENST00000397728.8 | |
LSS | NM_001001438.3 | c.2044C>T | p.Leu682Phe | missense_variant | 21/23 | ||
LSS | NM_001145436.2 | c.2011C>T | p.Leu671Phe | missense_variant | 21/22 | ||
LSS | NM_001145437.2 | c.1804C>T | p.Leu602Phe | missense_variant | 20/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LSS | ENST00000397728.8 | c.2044C>T | p.Leu682Phe | missense_variant | 21/22 | 1 | NM_002340.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249494Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135090
GnomAD3 exomes
AF:
AC:
2
AN:
249494
Hom.:
AF XY:
AC XY:
1
AN XY:
135090
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461292Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726850
GnomAD4 exome
AF:
AC:
4
AN:
1461292
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
726850
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380
GnomAD4 genome
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74380
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
?
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | The c.2044C>T (p.L682F) alteration is located in exon 21 (coding exon 21) of the LSS gene. This alteration results from a C to T substitution at nucleotide position 2044, causing the leucine (L) at amino acid position 682 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Benign
T;T;D;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MutPred
Loss of catalytic residue at L682 (P = 0.051);Loss of catalytic residue at L682 (P = 0.051);.;.;
MVP
MPC
0.31
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at