rs2738464

Variant names:

• chr19-11131631-G-C
• rs2738464
• NM_000527.5:c.*315G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11131631-G-C
• chr19-11131631-G-A
• chr19-11131631-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.*315G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 624,540 control chromosomes in the GnomAD database, including 221,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.80 (49823 hom., cov: 29)
  • Exomes 𝑓: 0.85 (171360 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.261
• Publications: 51 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-11131631-G-C is Benign according to our data. Variant chr19-11131631-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. 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
	LDLR	NM_000527.5	MANE Select	c.*315G>C		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*315G>C		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*315G>C		3_prime_UTR	Exon 17 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122048 AN: 151760 Hom.: 49799 Cov.: 29

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.881

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.819 AC: 59038 AN: 72086 AF XY: 0.823

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.725

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.881

Gnomad OTH exome AF: 0.849

GnomAD4 exome AF: 0.849 AC: 401273 AN: 472662 Hom.: 171360 Cov.: 2 AF XY: 0.848 AC XY: 213684 AN XY: 251960

African (AFR) AF: 0.659 AC: 8569 AN: 13010

American (AMR) AF: 0.818 AC: 18344 AN: 22424

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 12676 AN: 14888

East Asian (EAS) AF: 0.696 AC: 21958 AN: 31564

South Asian (SAS) AF: 0.795 AC: 38514 AN: 48472

European-Finnish (FIN) AF: 0.882 AC: 26632 AN: 30178

Middle Eastern (MID) AF: 0.847 AC: 1917 AN: 2262

European-Non Finnish (NFE) AF: 0.883 AC: 249695 AN: 282786

Other (OTH) AF: 0.848 AC: 22968 AN: 27078

GnomAD4 genome AF: 0.804 AC: 122126 AN: 151878 Hom.: 49823 Cov.: 29 AF XY: 0.804 AC XY: 59725 AN XY: 74248

African (AFR) AF: 0.658 AC: 27208 AN: 41348

American (AMR) AF: 0.818 AC: 12446 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2909 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3677 AN: 5162

South Asian (SAS) AF: 0.796 AC: 3819 AN: 4798

European-Finnish (FIN) AF: 0.881 AC: 9320 AN: 10580

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59923 AN: 67984

Other (OTH) AF: 0.831 AC: 1748 AN: 2104

Alfa AF: 0.846 Hom.: 7424

Bravo AF: 0.793

Asia WGS AF: 0.737 AC: 2563 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial hypercholesterolemia (2)
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.53
DANN	Benign	0.39
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2738464; hg19: chr19-11242307; COSMIC: COSV52943041; COSMIC: COSV52943041;