chr2-21026785-C-T
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000384.3(APOB):c.2244+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,611,938 control chromosomes in the GnomAD database, including 38 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000384.3 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, autosomal dominant, type BInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- familial hypobetalipoproteinemia 1Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.2244+3G>A | splice_region_variant, intron_variant | Intron 15 of 28 | 1 | NM_000384.3 | ENSP00000233242.1 | |||
APOB | ENST00000399256.4 | c.2244+3G>A | splice_region_variant, intron_variant | Intron 15 of 16 | 1 | ENSP00000382200.4 | ||||
APOB | ENST00000673739.2 | n.*1550+3G>A | splice_region_variant, intron_variant | Intron 14 of 24 | ENSP00000501110.2 | |||||
APOB | ENST00000673882.2 | n.*1550+3G>A | splice_region_variant, intron_variant | Intron 14 of 22 | ENSP00000501253.2 |
Frequencies
GnomAD3 genomes AF: 0.00852 AC: 1297AN: 152192Hom.: 18 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00214 AC: 536AN: 250970 AF XY: 0.00164 show subpopulations
GnomAD4 exome AF: 0.000828 AC: 1208AN: 1459628Hom.: 20 Cov.: 30 AF XY: 0.000693 AC XY: 503AN XY: 726304 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00853 AC: 1299AN: 152310Hom.: 18 Cov.: 32 AF XY: 0.00882 AC XY: 657AN XY: 74494 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:3
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BS1;BP6 -
not provided Benign:3
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Familial hypobetalipoproteinemia 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
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Hypercholesterolemia, autosomal dominant, type B Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial hypercholesterolemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at