21-46192252-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002340.6(LSS):c.1989-293T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 511,632 control chromosomes in the GnomAD database, including 104,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (28635 hom., cov: 32)
  • Exomes 𝑓: 0.65 (75425 hom.)
• Consequence: LSS NM_002340.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.537

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-46192252-A-C is Benign according to our data. Variant chr21-46192252-A-C is described in ClinVar as [Benign]. Clinvar id is 1287112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.1989-293T>G		intron_variant		ENST00000397728.8
LSS	NM_001001438.3	c.1989-293T>G		intron_variant
LSS	NM_001145436.2	c.1956-293T>G		intron_variant
LSS	NM_001145437.2	c.1749-293T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.1989-293T>G		intron_variant		1	NM_002340.6	P1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92914 AN: 151800 Hom.: 28630 Cov.: 32

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.645 AC: 232167 AN: 359714 Hom.: 75425 Cov.: 0 AF XY: 0.646 AC XY: 123989 AN XY: 192006

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.723

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.607

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.652

Gnomad4 OTH exome AF: 0.647

GnomAD4 genome AF: 0.612 AC: 92951 AN: 151918 Hom.: 28635 Cov.: 32 AF XY: 0.610 AC XY: 45294 AN XY: 74248

Gnomad4 AFR AF: 0.548

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.629

Alfa AF: 0.517 Hom.: 1474

Bravo AF: 0.605

Asia WGS AF: 0.607 AC: 2110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.73
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2839139; hg19: chr21-47612166;