Genetic Variant ABCB9:p.Lys765Arg (chr12-122929918-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019625.4(ABCB9):c.2294A>G(p.Lys765Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000517 in 1,548,726 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

ABCB9
NM_019625.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Variant links:

Genes affected

ABCB9 (HGNC:50): (ATP binding cassette subfamily B member 9) 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 intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This family member functions in the translocation of peptides from the cytosol into the lysosomal lumen. Alternative splicing of this gene results in distinct isoforms which are likely to have different substrate specificities. [provided by RefSeq, Jul 2011]

ABCB9 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0787586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB9	NM_019625.4 link	c.2294A>G	p.Lys765Arg	missense_variant	Exon 12 of 12	ENST00000280560.13	NP_062571.1	Q9NP78-1A0A024RBU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB9	ENST00000280560.13 link	c.2294A>G	p.Lys765Arg	missense_variant	Exon 12 of 12	1	NM_019625.4	ENSP00000280560.8		Q9NP78-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000144

AC:

AN:

208656

Hom.:

AF XY:

0.0000266

AC XY:

AN XY:

112862

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000501

AC:

AN:

1396494

Hom.:

Cov.:

AF XY:

0.00000582

AC XY:

AN XY:

686762

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000650

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74426

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2294A>G (p.K765R) alteration is located in exon 12 (coding exon 11) of the ABCB9 gene. This alteration results from a A to G substitution at nucleotide position 2294, causing the lysine (K) at amino acid position 765 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

0.064

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.;T;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.59

.;T;T;.;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.079

T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

-0.20

N;.;.;N;.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.85

N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.10

T;D;T;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.0010

B;.;B;B;.;B

Vest4

0.044

MVP

0.82

MPC

0.17

ClinPred

0.18

GERP RS

3.4

Varity_R

0.043

gMVP

0.50

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

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