Genetic Variant NM_001606.5:c.42C>G (chr9-137028099-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001606.5(ABCA2):c.42C>G(p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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_001606.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.620

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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ABCA2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_001606.5 link	c.42C>G	p.Asn14Lys	missense_variant	Exon 1 of 49	ENST00000341511.11	NP_001597.2	Q9BZC7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11 link	c.42C>G	p.Asn14Lys	missense_variant	Exon 1 of 49	5	NM_001606.5	ENSP00000344155.6		Q9BZC7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

842822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

389748

African (AFR)

AF:

0.00

AC:

AN:

15932

American (AMR)

AF:

0.00

AC:

AN:

1152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5406

East Asian (EAS)

AF:

0.00

AC:

AN:

4382

South Asian (SAS)

AF:

0.00

AC:

AN:

17368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1908

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

766624

Other (OTH)

AF:

0.00

AC:

AN:

27734

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual developmental disorder with poor growth and with or without seizures or ataxia

Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

.;D;D

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.84

T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.2

M;M;.

PhyloP100

0.62

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.56

.;P;.

Vest4

0.43

MutPred

0.59

Gain of methylation at N14 (P = 0.009);Gain of methylation at N14 (P = 0.009);Gain of methylation at N14 (P = 0.009);

MVP

0.82

MPC

0.11

ClinPred

0.95

GERP RS

1.1

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.079

gMVP

0.55

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.59

Position offset: 0

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