NM_002340.6:c.524G>A

Variant names:

• chr21-46221880-C-T
• rs2839158
• NM_002340.6:c.524G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002340.6(LSS):​c.524G>A​(p.Arg175Gln) variant causes a missense change. The variant allele was found at a frequency of 0.156 in 1,613,904 control chromosomes in the GnomAD database, including 20,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1640 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18942 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.98
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• alopecia-intellectual disability syndrome 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 44

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypotrichosis 14

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive palmoplantar keratoderma and congenital alopecia

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ENSG00000223901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020841062).
• BP6: Variant 21-46221880-C-T is Benign according to our data. Variant chr21-46221880-C-T is described in ClinVar as Benign. ClinVar VariationId is 677220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.524G>A	p.Arg175Gln	missense_variant	Exon 5 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.524G>A	p.Arg175Gln	missense_variant	Exon 5 of 23		NP_001001438.1
LSS	NM_001145436.2	c.491G>A	p.Arg164Gln	missense_variant	Exon 5 of 22		NP_001138908.1
LSS	NM_001145437.2	c.284G>A	p.Arg95Gln	missense_variant	Exon 4 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.524G>A	p.Arg175Gln	missense_variant	Exon 5 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21766 AN: 151964 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.136 AC: 34159 AN: 251468 AF XY: 0.137

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.0956

Gnomad FIN exome AF: 0.0888

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 230576 AN: 1461822 Hom.: 18942 Cov.: 34 AF XY: 0.156 AC XY: 113725 AN XY: 727208

African (AFR) AF: 0.134 AC: 4489 AN: 33476

American (AMR) AF: 0.123 AC: 5486 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3266 AN: 26134

East Asian (EAS) AF: 0.0838 AC: 3328 AN: 39698

South Asian (SAS) AF: 0.103 AC: 8907 AN: 86254

European-Finnish (FIN) AF: 0.0946 AC: 5053 AN: 53418

Middle Eastern (MID) AF: 0.176 AC: 1015 AN: 5762

European-Non Finnish (NFE) AF: 0.171 AC: 189897 AN: 1111964

Other (OTH) AF: 0.151 AC: 9135 AN: 60394

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152082 Hom.: 1640 Cov.: 32 AF XY: 0.137 AC XY: 10211 AN XY: 74348

African (AFR) AF: 0.132 AC: 5494 AN: 41478

American (AMR) AF: 0.137 AC: 2091 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.0909 AC: 470 AN: 5172

South Asian (SAS) AF: 0.0886 AC: 426 AN: 4808

European-Finnish (FIN) AF: 0.0875 AC: 926 AN: 10578

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11462 AN: 67962

Other (OTH) AF: 0.155 AC: 327 AN: 2116

Alfa AF: 0.158 Hom.: 7360

Bravo AF: 0.149

TwinsUK AF: 0.173 AC: 641

ALSPAC AF: 0.174 AC: 669

ESP6500AA AF: 0.135 AC: 597

ESP6500EA AF: 0.168 AC: 1444

ExAC AF: 0.136 AC: 16564

Asia WGS AF: 0.105 AC: 368 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

LSS-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.055	T;T;D;T;D
Sift4G	Benign	0.092	T;T;T;T;T
Polyphen		0.62	P;P;.;.;.
Vest4		0.23
MPC		0.47
ClinPred		0.030	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.71
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2839158; hg19: chr21-47641794; COSMIC: COSV62699775;