9-137008459-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001606.5(ABCA2):c.7232T>G(p.Leu2411Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000568 in 1,407,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ABCA2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA2	NM_001606.5	c.7232T>G	p.Leu2411Arg	missense_variant	48/49	ENST00000341511.11
ABCA2	NM_212533.3	c.7322T>G	p.Leu2441Arg	missense_variant	48/49
ABCA2	NM_001411042.1	c.7229T>G	p.Leu2410Arg	missense_variant	47/48
ABCA2	XM_047422921.1	c.7319T>G	p.Leu2440Arg	missense_variant	47/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA2	ENST00000341511.11	c.7232T>G	p.Leu2411Arg	missense_variant	48/49	5	NM_001606.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000601 AC: 1 AN: 166384 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 89526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000568 AC: 8 AN: 1407812 Hom.: 0 Cov.: 42 AF XY: 0.00000862 AC XY: 6 AN XY: 695742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.7322T>G (p.L2441R) alteration is located in exon 48 (coding exon 48) of the ABCA2 gene. This alteration results from a T to G substitution at nucleotide position 7322, causing the leucine (L) at amino acid position 2441 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.71	N;N;N;.;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Benign	0.099	T;T;T;T;D
Polyphen		0.99	.;D;.;.;.
Vest4		0.73
MutPred		0.22		.;Loss of stability (P = 0.0582);.;.;.;
MVP		0.80
MPC		0.99
ClinPred		0.59	D
GERP RS		4.1
Varity_R		0.31
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1019764433; hg19: chr9-139902911;