chr21-46194529-A-G

Variant names:

• chr21-46194529-A-G
• rs2254522
• NM_002340.6:c.1950T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002340.6(LSS):​c.1950T>C​(p.His650His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,500 control chromosomes in the GnomAD database, including 44,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5320 hom., cov: 35)
  • Exomes 𝑓: 0.22 (39026 hom.)
• Consequence: LSS NM_002340.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.66
• Publications: 38 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 21-46194529-A-G is Benign according to our data. Variant chr21-46194529-A-G is described in ClinVar as Benign. ClinVar VariationId is 677176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	NM_002340.6	MANE Select	c.1950T>C	p.His650His	synonymous	Exon 20 of 22	NP_002331.3
	LSS	NM_001001438.3		c.1950T>C	p.His650His	synonymous	Exon 20 of 23	NP_001001438.1
	LSS	NM_001145436.2		c.1917T>C	p.His639His	synonymous	Exon 20 of 22	NP_001138908.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.1950T>C	p.His650His	synonymous	Exon 20 of 22	ENSP00000380837.2
	LSS	ENST00000356396.8	TSL:1	c.1950T>C	p.His650His	synonymous	Exon 20 of 23	ENSP00000348762.3
	LSS	ENST00000457828.6	TSL:1	c.1710T>C	p.His570His	synonymous	Exon 19 of 21	ENSP00000409191.2

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38368 AN: 152118 Hom.: 5317 Cov.: 35

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.257 AC: 64412 AN: 250270 AF XY: 0.258

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.215 AC: 314667 AN: 1461264 Hom.: 39026 Cov.: 36 AF XY: 0.219 AC XY: 159331 AN XY: 726916

African (AFR) AF: 0.314 AC: 10512 AN: 33476

American (AMR) AF: 0.245 AC: 10928 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7487 AN: 26130

East Asian (EAS) AF: 0.626 AC: 24842 AN: 39690

South Asian (SAS) AF: 0.310 AC: 26726 AN: 86242

European-Finnish (FIN) AF: 0.217 AC: 11529 AN: 53014

Middle Eastern (MID) AF: 0.302 AC: 1742 AN: 5764

European-Non Finnish (NFE) AF: 0.186 AC: 206474 AN: 1111878

Other (OTH) AF: 0.239 AC: 14427 AN: 60384

GnomAD4 genome AF: 0.252 AC: 38382 AN: 152236 Hom.: 5320 Cov.: 35 AF XY: 0.257 AC XY: 19139 AN XY: 74426

African (AFR) AF: 0.314 AC: 13040 AN: 41552

American (AMR) AF: 0.248 AC: 3795 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1033 AN: 3470

East Asian (EAS) AF: 0.569 AC: 2933 AN: 5152

South Asian (SAS) AF: 0.320 AC: 1547 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2348 AN: 10614

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12888 AN: 68002

Other (OTH) AF: 0.249 AC: 526 AN: 2112

Alfa AF: 0.223 Hom.: 12837

Bravo AF: 0.258

Asia WGS AF: 0.390 AC: 1355 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.209

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		2.7
PromoterAI		-0.0028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2254522; hg19: chr21-47614443; COSMIC: COSV62700896; COSMIC: COSV62700896;