21-46228559-C-A

Variant names:

• chr21-46228559-C-A
• rs1487476965
• NM_002340.6:c.55G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002340.6(LSS):​c.55G>T​(p.Ala19Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24925742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.55G>T	p.Ala19Ser	missense_variant	Exon 2 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.55G>T	p.Ala19Ser	missense_variant	Exon 2 of 23		NP_001001438.1
LSS	NM_001145436.2	c.55G>T	p.Ala19Ser	missense_variant	Exon 2 of 22		NP_001138908.1
LSS	NM_001145437.2	c.-186G>T		5_prime_UTR_variant	Exon 1 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.55G>T	p.Ala19Ser	missense_variant	Exon 2 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443028 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T;T;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.63	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.67	P;P;.;.
Vest4		0.59
MutPred		0.19		Gain of phosphorylation at A19 (P = 0.0449);Gain of phosphorylation at A19 (P = 0.0449);Gain of phosphorylation at A19 (P = 0.0449);.;
MVP		0.42
MPC		0.61
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1487476965; hg19: chr21-47648473;