9-137008556-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001606.5(ABCA2):c.7135G>A(p.Ala2379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,606,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ABCA2
NM_001606.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.747

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, ABCA2

BP4

Computational evidence support a benign effect (MetaRNN=0.0065402985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCA2	NM_001606.5 linkuse as main transcript	c.7135G>A	p.Ala2379Thr	missense_variant	48/49	ENST00000341511.11
ABCA2	NM_212533.3 linkuse as main transcript	c.7225G>A	p.Ala2409Thr	missense_variant	48/49
ABCA2	NM_001411042.1 linkuse as main transcript	c.7132G>A	p.Ala2378Thr	missense_variant	47/48
ABCA2	XM_047422921.1 linkuse as main transcript	c.7222G>A	p.Ala2408Thr	missense_variant	47/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA2	ENST00000341511.11 linkuse as main transcript	c.7135G>A	p.Ala2379Thr	missense_variant	48/49	5	NM_001606.5	P3	Q9BZC7-3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000425

AC:

AN:

235298

Hom.:

AF XY:

0.0000468

AC XY:

AN XY:

128106

show subpopulations

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:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000752

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1454476

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

722770

show subpopulations

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000171

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000332

ExAC

AF:

0.0000333

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.7225G>A (p.A2409T) 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 7225, causing the alanine (A) at amino acid position 2409 to be replaced by a threonine (T). 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

0.066

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.82

T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0065

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N;N;.;N

REVEL

Benign

0.27

Sift

Benign

0.13

T;T;T;.;T

Sift4G

Benign

0.15

T;T;T;T;T

Polyphen

0.0

.;B;.;.;.

Vest4

0.10

MutPred

0.20

.;Loss of helix (P = 0.0376);.;.;.;

MVP

0.50

MPC

0.69

ClinPred

0.061

GERP RS

2.4

Varity_R

0.024

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over