9-137008459-A-C

Variant names:

• chr9-137008459-A-C
• rs1019764433
• NM_001606.5:c.7232T>G

Variant summary

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

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
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5	c.7232T>G	p.Leu2411Arg	missense_variant	Exon 48 of 49	ENST00000341511.11	NP_001597.2
ABCA2	NM_212533.3	c.7322T>G	p.Leu2441Arg	missense_variant	Exon 48 of 49		NP_997698.1
ABCA2	NM_001411042.1	c.7229T>G	p.Leu2410Arg	missense_variant	Exon 47 of 48		NP_001397971.1
ABCA2	XM_047422921.1	c.7319T>G	p.Leu2440Arg	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	c.7232T>G	p.Leu2411Arg	missense_variant	Exon 48 of 49	5	NM_001606.5	ENSP00000344155.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000601 AC: 1 AN: 166384 AF XY: 0.0000112

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32132

American (AMR) AF: 0.00 AC: 0 AN: 36778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 36576

South Asian (SAS) AF: 0.00 AC: 0 AN: 80248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48102

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5716

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1084638

Other (OTH) AF: 0.0000171 AC: 1 AN: 58376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.33	.;T;T;.;T
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
MutationAssessor	Benign	1.8	.;L;.;.;.
PhyloP100		7.2
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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1019764433; hg19: chr9-139902911;