Genetic Variant ABCA2:n.336G>A (chr9-137008345-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001606.5(ABCA2):c.7275+71G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,373,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ABCA2
NM_001606.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.49

Publications

6 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ABCA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5 link	c.7275+71G>A	intron_variant	Intron 48 of 48	ENST00000341511.11	NP_001597.2	Q9BZC7-3
ABCA2	NM_212533.3 link	c.7365+71G>A	intron_variant	Intron 48 of 48		NP_997698.1	Q9BZC7-4
ABCA2	NM_001411042.1 link	c.7272+71G>A	intron_variant	Intron 47 of 47		NP_001397971.1
ABCA2	XM_047422921.1 link	c.7362+71G>A	intron_variant	Intron 47 of 47		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11 link	c.7275+71G>A		intron_variant	Intron 48 of 48	5	NM_001606.5	ENSP00000344155.6		Q9BZC7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1373916

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679036

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000321

AC:

AN:

31160

American (AMR)

AF:

0.00

AC:

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25056

East Asian (EAS)

AF:

0.00

AC:

AN:

35642

South Asian (SAS)

AF:

0.00

AC:

AN:

78710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062728

Other (OTH)

AF:

0.00

AC:

AN:

57358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

12085

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.59

(source)

DANN

Benign

0.88

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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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9-137008345-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over