21-46215262-T-G

Variant names:

• chr21-46215262-T-G
• rs34115287
• NM_002340.6:c.929A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002340.6(LSS):​c.929A>C​(p.His310Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H310R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11579546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.929A>C	p.His310Pro	missense_variant	Exon 9 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.929A>C	p.His310Pro	missense_variant	Exon 9 of 23		NP_001001438.1
LSS	NM_001145436.2	c.896A>C	p.His299Pro	missense_variant	Exon 9 of 22		NP_001138908.1
LSS	NM_001145437.2	c.689A>C	p.His230Pro	missense_variant	Exon 8 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.929A>C	p.His310Pro	missense_variant	Exon 9 of 22	1	NM_002340.6	ENSP00000380837.2
LSS	ENST00000356396.8	c.929A>C	p.His310Pro	missense_variant	Exon 9 of 23	1		ENSP00000348762.3
LSS	ENST00000457828.6	c.689A>C	p.His230Pro	missense_variant	Exon 8 of 21	1		ENSP00000409191.2
LSS	ENST00000522411.5	c.896A>C	p.His299Pro	missense_variant	Exon 9 of 22	2		ENSP00000429133.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.4
DANN	Benign	0.37
DEOGEN2	Benign	0.022	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.66	.;T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0040	B;B;.;.
Vest4		0.40
MutPred		0.35		Loss of disorder (P = 0.125);Loss of disorder (P = 0.125);.;.;
MVP		0.25
MPC		0.45
ClinPred		0.099	T
GERP RS		1.5
Varity_R		0.31
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs34115287; hg19: chr21-47635176;