21-46191897-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002340.6(LSS):c.2051A>G(p.Asn684Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000098 (1 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.34

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21491688).
• BP6: Variant 21-46191897-T-C is Benign according to our data. Variant chr21-46191897-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2352802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.2051A>G	p.Asn684Ser	missense_variant	21/22	ENST00000397728.8
LSS	NM_001001438.3	c.2051A>G	p.Asn684Ser	missense_variant	21/23
LSS	NM_001145436.2	c.2018A>G	p.Asn673Ser	missense_variant	21/22
LSS	NM_001145437.2	c.1811A>G	p.Asn604Ser	missense_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.2051A>G	p.Asn684Ser	missense_variant	21/22	1	NM_002340.6	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249188 Hom.: 0 AF XY: 0.0000963 AC XY: 13 AN XY: 134956

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000989

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000888

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000979 AC: 143 AN: 1461172 Hom.: 1 Cov.: 31 AF XY: 0.0000881 AC XY: 64 AN XY: 726778

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74334

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.040	D;D;T;D
Sift4G	Benign	0.074	T;T;T;T
Polyphen		0.96	D;D;.;.
Vest4		0.17
MVP		0.40
MPC		0.24
ClinPred		0.047	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759825672; hg19: chr21-47611811;