21-46221880-C-T

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002340.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	NM_002340.6	MANE Select	c.524G>A	p.Arg175Gln	missense	Exon 5 of 22	NP_002331.3
	LSS	NM_001001438.3		c.524G>A	p.Arg175Gln	missense	Exon 5 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.491G>A	p.Arg164Gln	missense	Exon 5 of 22	NP_001138908.1	P48449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.524G>A	p.Arg175Gln	missense	Exon 5 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.524G>A	p.Arg175Gln	missense	Exon 5 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.284G>A	p.Arg95Gln	missense	Exon 4 of 21	ENSP00000409191.2	P48449-2

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	LSS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.055	T
Sift4G	Benign	0.092	T
Polyphen		0.62	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;