12-124782767-C-G

Position:

• chr12-124782767-C-G

Variant summary

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

The NM_005505.5(SCARB1):​c.1446G>C​(p.Lys482Asn) 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. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCARB1 NM_005505.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

Genes affected

SCARB1 (HGNC:1664): (scavenger receptor class B member 1) The protein encoded by this gene is a plasma membrane receptor for high density lipoprotein cholesterol (HDL). The encoded protein mediates cholesterol transfer to and from HDL. In addition, this protein is a receptor for hepatitis C virus glycoprotein E2 and facilitates cell entry by the virus, SARS-CoV2. [provided by RefSeq, Oct 2021]

SCARB1 (HGNC:):

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=0.18044469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB1	NM_005505.5	c.1446G>C	p.Lys482Asn	missense_variant	12/13	ENST00000261693.11	NP_005496.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB1	ENST00000261693.11	c.1446G>C	p.Lys482Asn	missense_variant	12/13	1	NM_005505.5	ENSP00000261693.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.1446G>C (p.K482N) alteration is located in exon 12 (coding exon 12) of the SCARB1 gene. This alteration results from a G to C substitution at nucleotide position 1446, causing the lysine (K) at amino acid position 482 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	.;T
Eigen	Benign	0.021
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.16
Sift	Benign	0.44	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.63	P;P
Vest4		0.25
MutPred		0.15		.;Loss of methylation at K454 (P = 0.0264);
MVP		0.75
MPC		0.66
ClinPred		0.97	D
GERP RS		4.5
gMVP		0.15

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: rs746306162; hg19: chr12-125267313;