Genetic Variant NM_022437.3:c.322+550G>A (chr2-43846861-G-A) – 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+550G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0675 in 187,758 control chromosomes in the GnomAD database, including 498 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 0.068 ( 421 hom., cov: 32)

Exomes 𝑓: 0.063 ( 77 hom. )

Consequence

ABCG8
NM_022437.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

29 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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.322+550G>A		intron_variant	Intron 3 of 12	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.322+550G>A		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+550G>A	intron_variant	Intron 3 of 12	1	NM_022437.3	ENSP00000272286.2	Q9H221-1
ABCG8	ENST00000643284.1 link	n.1329G>A	non_coding_transcript_exon_variant	Exon 3 of 3
ABCG8	ENST00000644611.1 link	c.334+550G>A	intron_variant	Intron 3 of 8			ENSP00000495423.1	A0A2R8Y6M1

Frequencies

GnomAD3 genomes

AF:

0.0685

AC:

10413

AN:

152052

Hom.:

421

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0822

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0999

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.0355

Gnomad FIN

AF:

0.0874

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0619

Gnomad OTH

AF:

0.0608

GnomAD4 exome

AF:

0.0633

AC:

2252

AN:

35588

Hom.:

Cov.:

AF XY:

0.0615

AC XY:

1109

AN XY:

18030

show subpopulations

African (AFR)

AF:

0.0782

AC:

AN:

908

American (AMR)

AF:

0.104

AC:

351

AN:

3384

Ashkenazi Jewish (ASJ)

AF:

0.0866

AC:

AN:

670

East Asian (EAS)

AF:

0.0109

AC:

AN:

2382

South Asian (SAS)

AF:

0.0341

AC:

134

AN:

3930

European-Finnish (FIN)

AF:

0.0853

AC:

132

AN:

1548

Middle Eastern (MID)

AF:

0.0600

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.0652

AC:

1352

AN:

20752

Other (OTH)

AF:

0.0637

AC:

122

AN:

1914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.0685

AC:

10423

AN:

152170

Hom.:

421

Cov.:

AF XY:

0.0680

AC XY:

5061

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0821

AC:

3408

AN:

41488

American (AMR)

AF:

0.0716

AC:

1095

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0999

AC:

347

AN:

3472

East Asian (EAS)

AF:

0.0154

AC:

AN:

5186

South Asian (SAS)

AF:

0.0355

AC:

171

AN:

4816

European-Finnish (FIN)

AF:

0.0874

AC:

926

AN:

10596

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0619

AC:

4212

AN:

68012

Other (OTH)

AF:

0.0602

AC:

127

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

493

986

1480

1973

2466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0664

Hom.:

1128

Bravo

AF:

0.0715

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.6

(source)

DANN

Benign

0.62

PhyloP100

1.6

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