2-241236773-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005336.6(HDLBP):c.2750-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,712 control chromosomes in the GnomAD database, including 10,299 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (655 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9644 hom.)
• Consequence: HDLBP NM_005336.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001187
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.13

Genes affected

HDLBP (HGNC:4857): (high density lipoprotein binding protein) The protein encoded by this gene binds high density lipoprotein (HDL) and may function to regulate excess cholesterol levels in cells. The encoded protein also binds RNA and can induce heterochromatin formation. [provided by RefSeq, Mar 2016]

ANO7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-241236773-G-C is Benign according to our data. Variant chr2-241236773-G-C is described in ClinVar as [Benign]. Clinvar id is 3055900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDLBP	NM_005336.6	c.2750-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310931.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDLBP	ENST00000310931.10	c.2750-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005336.6	P1

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 12483 AN: 152108 Hom.: 655 Cov.: 31

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0670

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0926

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0967

GnomAD3 exomes AF: 0.0977 AC: 24450 AN: 250336 Hom.: 1403 AF XY: 0.103 AC XY: 13936 AN XY: 135270

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0434

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.0629

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.0968

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.111 AC: 162657 AN: 1460486 Hom.: 9644 Cov.: 33 AF XY: 0.113 AC XY: 81798 AN XY: 726574

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.0452

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0820 AC: 12477 AN: 152226 Hom.: 655 Cov.: 31 AF XY: 0.0821 AC XY: 6106 AN XY: 74410

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.0667

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0926

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0990

Alfa AF: 0.112 Hom.: 333

Bravo AF: 0.0772

Asia WGS AF: 0.110 AC: 383 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HDLBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.1
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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: rs2305071; hg19: chr2-242176188; COSMIC: COSV60495780; COSMIC: COSV60495780;