Genetic Variant NM_022437.3:c.322+981C>T (chr2-43847292-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022437.3(ABCG8):c.322+981C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 152,122 control chromosomes in the GnomAD database, including 44,996 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 44994 hom., cov: 32)

Exomes 𝑓: 0.75 ( 2 hom. )

Consequence

ABCG8
NM_022437.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

Publications

83 publications found

Variant links:

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 Gene-Disease associations (from GenCC):

sitosterolemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
sitosterolemia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.322+981C>T		intron_variant	Intron 3 of 12	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.322+981C>T		intron_variant	Intron 3 of 12		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCG8	ENST00000272286.4 link	c.322+981C>T	intron_variant	Intron 3 of 12	1	NM_022437.3	ENSP00000272286.2	Q9H221-1
ABCG8	ENST00000643284.1 link	n.1760C>T	non_coding_transcript_exon_variant	Exon 3 of 3
ABCG8	ENST00000644611.1 link	c.334+981C>T	intron_variant	Intron 3 of 8			ENSP00000495423.1	A0A2R8Y6M1

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116061

AN:

151996

Hom.:

44935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.869

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.767

Gnomad ASJ

AF:

0.730

Gnomad EAS

AF:

0.994

Gnomad SAS

AF:

0.770

Gnomad FIN

AF:

0.792

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.681

Gnomad OTH

AF:

0.734

GnomAD4 exome

AF:

0.750

AC:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.764

AC:

116175

AN:

152114

Hom.:

44994

Cov.:

AF XY:

0.771

AC XY:

57346

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.869

AC:

36059

AN:

41514

American (AMR)

AF:

0.768

AC:

11730

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.730

AC:

2531

AN:

3468

East Asian (EAS)

AF:

0.994

AC:

5144

AN:

5174

South Asian (SAS)

AF:

0.769

AC:

3696

AN:

4806

European-Finnish (FIN)

AF:

0.792

AC:

8373

AN:

10578

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.681

AC:

46305

AN:

67978

Other (OTH)

AF:

0.738

AC:

1555

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1362

2724

4086

5448

6810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.713

Hom.:

117616

Bravo

AF:

0.769

Asia WGS

AF:

0.889

AC:

3090

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over