16-48083962-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001393797.1(ABCC12):c.3940C>A(p.Arg1314Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC12 NM_001393797.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

Genes affected

ABCC12 (HGNC:14640): (ATP binding cassette subfamily C member 12) This gene is a member of the superfamily of ATP-binding cassette (ABC) transporters and the encoded protein contains two ATP-binding domains and 12 transmembrane regions. 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, and White. This gene is a member of the MRP subfamily which is involved in multi-drug resistance. This gene and another subfamily member are arranged head-to-tail on chromosome 16q12.1. Increased expression of this gene is associated with breast cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC12	NM_001393797.1	c.3940C>A	p.Arg1314Ser	missense_variant	30/31	ENST00000311303.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC12	ENST00000311303.8	c.3940C>A	p.Arg1314Ser	missense_variant	30/31	1	NM_001393797.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.3940C>A (p.R1314S) alteration is located in exon 28 (coding exon 28) of the ABCC12 gene. This alteration results from a C to A substitution at nucleotide position 3940, causing the arginine (R) at amino acid position 1314 to be replaced by a serine (S). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.92		Loss of sheet (P = 0.1158);
MVP		0.82
MPC		0.61
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.75

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: chr16-48117873;