9-137008510-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001606.5(ABCA2):c.7181G>A(p.Arg2394Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,586,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: ABCA2 NM_001606.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.86

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ABCA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.042449564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA2	NM_001606.5	c.7181G>A	p.Arg2394Gln	missense_variant	48/49	ENST00000341511.11
ABCA2	NM_212533.3	c.7271G>A	p.Arg2424Gln	missense_variant	48/49
ABCA2	NM_001411042.1	c.7178G>A	p.Arg2393Gln	missense_variant	47/48
ABCA2	XM_047422921.1	c.7268G>A	p.Arg2423Gln	missense_variant	47/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA2	ENST00000341511.11	c.7181G>A	p.Arg2394Gln	missense_variant	48/49	5	NM_001606.5	P3

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000609 AC: 123 AN: 202012 Hom.: 0 AF XY: 0.000621 AC XY: 68 AN XY: 109544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.000267

Gnomad SAS exome AF: 0.0000764

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000970

GnomAD4 exome AF: 0.00123 AC: 1766 AN: 1433768 Hom.: 3 Cov.: 42 AF XY: 0.00120 AC XY: 856 AN XY: 710598

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.000339

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.0000807

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00156 AC: 13

ExAC AF: 0.000461 AC: 55

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.7271G>A (p.R2424Q) alteration is located in exon 48 (coding exon 48) of the ABCA2 gene. This alteration results from a G to A substitution at nucleotide position 7271, causing the arginine (R) at amino acid position 2424 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ABCA2-related conditions. This variant is present in population databases (rs55971316, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2424 of the ABCA2 protein (p.Arg2424Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.27	N;N;N;.;N
REVEL	Benign	0.28
Sift	Uncertain	0.029	D;D;D;.;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.47
MVP		0.72
MPC		0.78
ClinPred		0.081	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55971316; hg19: chr9-139902962;