Genetic Variant ABCA2:n.135C>T (chr9-137028781-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_212533.3(ABCA2):c.92C>T(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ABCA2
NM_212533.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.510

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 links:

LINC02908 (HGNC:31426): (long intergenic non-protein coding RNA 2908)

LINC02908 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0556401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ABCA2	NM_212533.3 link	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 49	NP_997698.1	Q9BZC7-4
ABCA2	XM_047422921.1 link	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 48	XP_047278877.1
LINC02908	NR_171031.1 link	n.448+870G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ABCA2	ENST00000459850.5 link	n.135C>T		non_coding_transcript_exon_variant	Exon 1 of 47	1
ABCA2	ENST00000487109.5 link	n.92C>T		non_coding_transcript_exon_variant	Exon 1 of 47	1	ENSP00000418662.1	E9PGB2
ABCA2	ENST00000614293.5 link	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 49	5	ENSP00000481105.2	Q9BZC7-4A0A087WXK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1139446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

562548

African (AFR)

AF:

0.00

AC:

AN:

20854

American (AMR)

AF:

0.00

AC:

AN:

19512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14130

East Asian (EAS)

AF:

0.00

AC:

AN:

11556

South Asian (SAS)

AF:

0.00

AC:

AN:

71850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

925966

Other (OTH)

AF:

0.00

AC:

AN:

40794

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 13, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.18

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.51

Vest4

0.12

MVP

0.082

ClinPred

0.11

GERP RS

-0.29

PromoterAI

0.011

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over