chr21-46228456-G-C

Variant names:

• chr21-46228456-G-C
• rs373275028
• NM_002340.6:c.158C>G

Variant summary

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

The NM_002340.6(LSS):​c.158C>G​(p.Ala53Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,174 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 6.9e-7 (0 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82

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=0.2562406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.158C>G	p.Ala53Gly	missense_variant	Exon 2 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.158C>G	p.Ala53Gly	missense_variant	Exon 2 of 23		NP_001001438.1
LSS	NM_001145436.2	c.158C>G	p.Ala53Gly	missense_variant	Exon 2 of 22		NP_001138908.1
LSS	NM_001145437.2	c.-83C>G		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.158C>G	p.Ala53Gly	missense_variant	Exon 2 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000435 AC: 1 AN: 229668 Hom.: 0 AF XY: 0.00000787 AC XY: 1 AN XY: 127120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451174 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722376

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;.;.
Eigen	Benign	-0.030
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.095
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.67	P;P;.;.
Vest4		0.34
MutPred		0.48		Loss of stability (P = 0.0596);Loss of stability (P = 0.0596);Loss of stability (P = 0.0596);.;
MVP		0.52
MPC		0.29
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.51
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs373275028; hg19: chr21-47648370;