21-46191885-G-A

Position:

• chr21-46191885-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002340.6(LSS):​c.2063C>T​(p.Pro688Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,612,632 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (14 hom., cov: 33)
  • Exomes 𝑓: 0.018 (277 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.54

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009421557).
• BP6: Variant 21-46191885-G-A is Benign according to our data. Variant chr21-46191885-G-A is described in ClinVar as [Benign]. Clinvar id is 668540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0127 (1937/152300) while in subpopulation SAS AF= 0.0228 (110/4828). AF 95% confidence interval is 0.0193. There are 14 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.2063C>T	p.Pro688Leu	missense_variant	21/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.2063C>T	p.Pro688Leu	missense_variant	21/23		NP_001001438.1
LSS	NM_001145436.2	c.2030C>T	p.Pro677Leu	missense_variant	21/22		NP_001138908.1
LSS	NM_001145437.2	c.1823C>T	p.Pro608Leu	missense_variant	20/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.2063C>T	p.Pro688Leu	missense_variant	21/22	1	NM_002340.6	ENSP00000380837	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152182 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0158 AC: 3920 AN: 247854 Hom.: 44 AF XY: 0.0174 AC XY: 2334 AN XY: 134254

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.00751

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0259

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0179 AC: 26123 AN: 1460332 Hom.: 277 Cov.: 31 AF XY: 0.0185 AC XY: 13432 AN XY: 726240

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00773

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0241

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0127 AC: 1937 AN: 152300 Hom.: 14 Cov.: 33 AF XY: 0.0125 AC XY: 929 AN XY: 74484

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0188 Hom.: 55

Bravo AF: 0.0120

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0214 AC: 184

ExAC AF: 0.0161 AC: 1955

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;D
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.5	D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.51	T;T;D;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.13
MPC		0.95
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.68

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: rs17293705; hg19: chr21-47611799;