9-137008501-G-A

Position:

chr9-137008501-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001606.5(ABCA2):c.7190C>T(p.Pro2397Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,428,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ABCA2
NM_001606.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.41

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:

ABCA2 (HGNC:):

ABCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCA2. . Gene score misZ 4.9116 (greater than the threshold 3.09). Trascript score misZ 3.725 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, intellectual developmental disorder with poor growth and with or without seizures or ataxia.

BP4

Computational evidence support a benign effect (MetaRNN=0.27290836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA2	NM_001606.5 linkuse as main transcript	c.7190C>T	p.Pro2397Leu	missense_variant	48/49	ENST00000341511.11	NP_001597.2	Q9BZC7-3
ABCA2	NM_212533.3 linkuse as main transcript	c.7280C>T	p.Pro2427Leu	missense_variant	48/49		NP_997698.1	Q9BZC7-4
ABCA2	NM_001411042.1 linkuse as main transcript	c.7187C>T	p.Pro2396Leu	missense_variant	47/48		NP_001397971.1
ABCA2	XM_047422921.1 linkuse as main transcript	c.7277C>T	p.Pro2426Leu	missense_variant	47/48		XP_047278877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000341511.11 linkuse as main transcript	c.7190C>T	p.Pro2397Leu	missense_variant	48/49	5	NM_001606.5	ENSP00000344155.6		Q9BZC7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000103

AC:

AN:

193770

Hom.:

AF XY:

0.0000191

AC XY:

AN XY:

104930

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000693

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1428750

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000752

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000168

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

Nov 30, 2022

The c.7280C>T (p.P2427L) alteration is located in exon 48 (coding exon 48) of the ABCA2 gene. This alteration results from a C to T substitution at nucleotide position 7280, causing the proline (P) at amino acid position 2427 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T;T;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

.;L;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

N;N;N;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.010

D;D;D;.;D

Sift4G

Uncertain

0.038

D;D;D;T;T

Polyphen

0.030

.;B;.;.;.

Vest4

0.38

MVP

0.50

MPC

0.69

ClinPred

0.38

GERP RS

4.1

Varity_R

0.14

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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