21-46191371-T-C

Position:

• chr21-46191371-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002340.6(LSS):​c.2068-136A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 917,238 control chromosomes in the GnomAD database, including 7,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1407 hom., cov: 33)
  • Exomes 𝑓: 0.12 (6526 hom.)
• Consequence: LSS NM_002340.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21

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]

LSS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-46191371-T-C is Benign according to our data. Variant chr21-46191371-T-C is described in ClinVar as [Benign]. Clinvar id is 1277484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.2068-136A>G		intron_variant		ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.2068-136A>G		intron_variant			NP_001001438.1
LSS	NM_001145436.2	c.2035-136A>G		intron_variant			NP_001138908.1
LSS	NM_001145437.2	c.1828-136A>G		intron_variant			NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.2068-136A>G		intron_variant		1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19365 AN: 152070 Hom.: 1409 Cov.: 33

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0984

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.119 AC: 91314 AN: 765050 Hom.: 6526 AF XY: 0.118 AC XY: 46860 AN XY: 395956

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.0785

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.000251

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0602

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.127 AC: 19373 AN: 152188 Hom.: 1407 Cov.: 33 AF XY: 0.120 AC XY: 8966 AN XY: 74412

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0983

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0552

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.151

Alfa AF: 0.123 Hom.: 162

Bravo AF: 0.135

Asia WGS AF: 0.0470 AC: 167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.55
DANN	Benign	0.22

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: rs73144744; hg19: chr21-47611285;