21-46228476-G-C

Variant names:

• chr21-46228476-G-C
• rs572893842
• NM_002340.6:c.138C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002340.6(LSS):​c.138C>G​(p.Arg46Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,058 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. Synonymous variant affecting the same amino acid position (i.e. R46R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LSS NM_002340.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.949
• 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]

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=-0.949 with no splicing effect.

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.138C>G	p.Arg46Arg	synonymous	Exon 2 of 22	NP_002331.3
	LSS	NM_001001438.3		c.138C>G	p.Arg46Arg	synonymous	Exon 2 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.138C>G	p.Arg46Arg	synonymous	Exon 2 of 22	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.138C>G	p.Arg46Arg	synonymous	Exon 2 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.138C>G	p.Arg46Arg	synonymous	Exon 2 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.-103C>G		5_prime_UTR	Exon 1 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228626 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451058 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722300

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111560

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.0
DANN	Benign	0.66
PhyloP100		-0.95
PromoterAI		-0.0051	Neutral

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

Other links and lift over

dbSNP: rs572893842; hg19: chr21-47648390;