Genetic Variant ABCA2:p.Leu2411Pro (chr9-137008459-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001606.5(ABCA2):c.7232T>C(p.Leu2411Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2411R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ABCA2
NM_001606.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.20

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5 link	c.7232T>C	p.Leu2411Pro	missense_variant	Exon 48 of 49	ENST00000341511.11	NP_001597.2	Q9BZC7-3
ABCA2	NM_212533.3 link	c.7322T>C	p.Leu2441Pro	missense_variant	Exon 48 of 49		NP_997698.1	Q9BZC7-4
ABCA2	NM_001411042.1 link	c.7229T>C	p.Leu2410Pro	missense_variant	Exon 47 of 48		NP_001397971.1
ABCA2	XM_047422921.1 link	c.7319T>C	p.Leu2440Pro	missense_variant	Exon 47 of 48		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11 link	c.7232T>C	p.Leu2411Pro	missense_variant	Exon 48 of 49	5	NM_001606.5	ENSP00000344155.6		Q9BZC7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1407810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32132

American (AMR)

AF:

0.00

AC:

AN:

36778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36576

South Asian (SAS)

AF:

0.00

AC:

AN:

80248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084638

Other (OTH)

AF:

0.00

AC:

AN:

58376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T;T;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.8

.;L;.;.;.

PhyloP100

7.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.95

N;N;N;.;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0050

D;D;D;.;T

Sift4G

Uncertain

0.0090

D;D;D;D;D

Polyphen

0.99

.;D;.;.;.

Vest4

0.75

MVP

0.77

MPC

1.1

ClinPred

0.92

GERP RS

4.1

Varity_R

0.32

gMVP

0.62

Mutation Taster

=73/27

polymorphism

(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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9-137008459-A-G

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