Genetic Variant ABCA2:p.Asp679Asp (chr9-137018032-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001606.5(ABCA2):c.2037T>C(p.Asp679Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,612,726 control chromosomes in the GnomAD database, including 760,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70892 hom., cov: 33)

Exomes 𝑓: 0.97 ( 689854 hom. )

Consequence

ABCA2
NM_001606.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.603

Publications

30 publications found

Variant links:

Genes affected

ABCA2 (HGNC:32): (ATP binding cassette subfamily A member 2) The membrane-associated 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 intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ABCA2 Gene-Disease associations (from GenCC):

intellectual developmental disorder with poor growth and with or without seizures or ataxia
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ABCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

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

BP6

Variant 9-137018032-A-G is Benign according to our data. Variant chr9-137018032-A-G is described in ClinVar as Benign. ClinVar VariationId is 1185362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.603 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001606.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA2	NM_001606.5	MANE Select	c.2037T>C	p.Asp679Asp	synonymous	Exon 15 of 49	NP_001597.2
ABCA2	NM_212533.3		c.2127T>C	p.Asp709Asp	synonymous	Exon 15 of 49	NP_997698.1	Q9BZC7-4
ABCA2	NM_001411042.1		c.2034T>C	p.Asp678Asp	synonymous	Exon 14 of 48	NP_001397971.1	Q9BZC7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA2	ENST00000341511.11	TSL:5 MANE Select	c.2037T>C	p.Asp679Asp	synonymous	Exon 15 of 49	ENSP00000344155.6	Q9BZC7-3
ABCA2	ENST00000459850.5	TSL:1	n.2167T>C		non_coding_transcript_exon	Exon 14 of 47
ABCA2	ENST00000479446.5	TSL:1	n.84T>C		non_coding_transcript_exon	Exon 2 of 35	ENSP00000420084.1	H0Y8D6

Frequencies

GnomAD3 genomes

AF:

0.965

AC:

146815

AN:

152192

Hom.:

70841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.942

Gnomad AMI

AF:

0.986

Gnomad AMR

AF:

0.981

Gnomad ASJ

AF:

0.969

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.977

Gnomad FIN

AF:

0.966

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.971

Gnomad OTH

AF:

0.967

GnomAD2 exomes

AF:

0.975

AC:

241477

AN:

247686

AF XY:

0.975

show subpopulations

Gnomad AFR exome

AF:

0.942

Gnomad AMR exome

AF:

0.990

Gnomad ASJ exome

AF:

0.973

Gnomad EAS exome

AF:

0.996

Gnomad FIN exome

AF:

0.971

Gnomad NFE exome

AF:

0.972

Gnomad OTH exome

AF:

0.975

GnomAD4 exome

AF:

0.972

AC:

1419411

AN:

1460416

Hom.:

689854

Cov.:

AF XY:

0.972

AC XY:

706070

AN XY:

726488

show subpopulations

African (AFR)

AF:

0.938

AC:

31389

AN:

33478

American (AMR)

AF:

0.989

AC:

44245

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.974

AC:

25442

AN:

26134

East Asian (EAS)

AF:

0.998

AC:

39609

AN:

39700

South Asian (SAS)

AF:

0.977

AC:

84294

AN:

86256

European-Finnish (FIN)

AF:

0.971

AC:

50558

AN:

52056

Middle Eastern (MID)

AF:

0.974

AC:

5618

AN:

5766

European-Non Finnish (NFE)

AF:

0.971

AC:

1079672

AN:

1111942

Other (OTH)

AF:

0.970

AC:

58584

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

2654

5308

7961

10615

13269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21654

43308

64962

86616

108270

<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:

0.965

AC:

146927

AN:

152310

Hom.:

70892

Cov.:

AF XY:

0.965

AC XY:

71896

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.942

AC:

39143

AN:

41562

American (AMR)

AF:

0.981

AC:

15019

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.969

AC:

3366

AN:

3472

East Asian (EAS)

AF:

0.997

AC:

5154

AN:

5172

South Asian (SAS)

AF:

0.977

AC:

4722

AN:

4832

European-Finnish (FIN)

AF:

0.966

AC:

10266

AN:

10624

Middle Eastern (MID)

AF:

0.966

AC:

284

AN:

294

European-Non Finnish (NFE)

AF:

0.971

AC:

66030

AN:

68024

Other (OTH)

AF:

0.968

AC:

2044

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

288

576

863

1151

1439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.970

Hom.:

180250

Bravo

AF:

0.965

Asia WGS

AF:

0.981

AC:

3411

AN:

3478

EpiCase

AF:

0.969

EpiControl

AF:

0.971

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual developmental disorder with poor growth and with or without seizures or ataxia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.1

(source)

DANN

Benign

0.45

PhyloP100

-0.60

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over