12-122940265-G-C

Position:

• chr12-122940265-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_019625.4(ABCB9):​c.1589C>G​(p.Ser530Cys) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCB9 NM_019625.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0720

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16341972).
• BP6: Variant 12-122940265-G-C is Benign according to our data. Variant chr12-122940265-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3126906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB9	NM_019625.4	c.1589C>G	p.Ser530Cys	missense_variant	9/12	ENST00000280560.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB9	ENST00000280560.13	c.1589C>G	p.Ser530Cys	missense_variant	9/12	1	NM_019625.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Uncertain	0.75	.;.;D;.;.;D;D;D;D;D;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.68	T;T;.;T;T;.;T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Benign	1.4	L;L;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.088	T;T;T;T;T;T;T;T;D;D;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.0, 0.0010	.;.;B;.;B;B;.;B;.;.;.
Vest4		0.23
MutPred		0.46		Gain of catalytic residue at K533 (P = 5e-04);Gain of catalytic residue at K533 (P = 5e-04);Gain of catalytic residue at K533 (P = 5e-04);.;.;Gain of catalytic residue at K533 (P = 5e-04);Gain of catalytic residue at K533 (P = 5e-04);Gain of catalytic residue at K533 (P = 5e-04);.;.;.;
MVP		0.75
MPC		0.20
ClinPred		0.035	T
GERP RS		-0.46
Varity_R		0.13
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-123424812;