21-46228592-G-C

Variant names:

• chr21-46228592-G-C
• NM_002340.6:c.22C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002340.6(LSS):​c.22C>G​(p.Arg8Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41654417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.22C>G	p.Arg8Gly	missense_variant	Exon 2 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.22C>G	p.Arg8Gly	missense_variant	Exon 2 of 23		NP_001001438.1
LSS	NM_001145436.2	c.22C>G	p.Arg8Gly	missense_variant	Exon 2 of 22		NP_001138908.1
LSS	NM_001145437.2	c.-219C>G		5_prime_UTR_variant	Exon 1 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.22C>G	p.Arg8Gly	missense_variant	Exon 2 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alopecia-intellectual disability syndrome 4 Uncertain:1

Feb 05, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited heterozygous c.22C>G, p.Arg8Gly missense variant identified in the LSS gene has not been reported in affected individuals in the literature or in the ClinVar database. The variant isabsent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects a moderately conserved residue. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 33, REVEL score = 0.192). Based on the available evidence, the inherited heterozygous c.22C>G, p.Arg8Gly missense variant identified in the LSS gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.73
MutPred		0.23		Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);.;
MVP		0.52
MPC		1.1
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.62
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47648506;