21-46191631-G-A

Position:

• chr21-46191631-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002340.6(LSS):​c.2067+250C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 152,244 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.026 (66 hom., cov: 33)
• Consequence: LSS NM_002340.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.260

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=-0.86).
• BP6: Variant 21-46191631-G-A is Benign according to our data. Variant chr21-46191631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1211649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0261 (3967/152244) while in subpopulation AFR AF= 0.0372 (1546/41530). AF 95% confidence interval is 0.0357. There are 66 homozygotes in gnomad4. There are 1860 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.2067+250C>T		intron_variant		ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.2067+250C>T		intron_variant			NP_001001438.1
LSS	NM_001145436.2	c.2034+250C>T		intron_variant			NP_001138908.1
LSS	NM_001145437.2	c.1827+250C>T		intron_variant			NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.2067+250C>T		intron_variant		1	NM_002340.6	ENSP00000380837	P1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3967 AN: 152126 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0261 AC: 3967 AN: 152244 Hom.: 66 Cov.: 33 AF XY: 0.0250 AC XY: 1860 AN XY: 74436

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0103 Hom.: 6

Bravo AF: 0.0264

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.38
DANN	Benign	0.35

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: rs76715041; hg19: chr21-47611545;