16-48175312-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001370497.1(ABCC11):c.3644G>A(p.Arg1215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: ABCC11 NM_001370497.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

Genes affected

ABCC11 (HGNC:14639): (ATP binding cassette subfamily C member 11) The 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 ABC full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. The product of this gene participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides. In addition, a SNP in this gene is responsible for determination of human earwax type. This gene and family member ABCC12 are determined to be derived by duplication and are both localized to chromosome 16q12.1. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC11	NM_001370497.1	c.3644G>A	p.Arg1215Gln	missense_variant	26/30	ENST00000356608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC11	ENST00000356608.7	c.3644G>A	p.Arg1215Gln	missense_variant	26/30	1	NM_001370497.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251350 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135886

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.000296

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 20, 2023

The c.3644G>A (p.R1215Q) alteration is located in exon 26 (coding exon 25) of the ABCC11 gene. This alteration results from a G to A substitution at nucleotide position 3644, causing the arginine (R) at amino acid position 1215 to be replaced by a glutamine (Q). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Benign	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.96	D;.;.;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.93	P;D;D;D
Vest4		0.91
MutPred		0.96		Gain of ubiquitination at K1217 (P = 0.1375);Gain of ubiquitination at K1217 (P = 0.1375);Gain of ubiquitination at K1217 (P = 0.1375);Gain of ubiquitination at K1217 (P = 0.1375);
MVP		0.94
MPC		0.49
ClinPred		0.93	D
GERP RS		1.9
Varity_R		0.75
gMVP		0.91

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

Other links and lift over

dbSNP: rs572621805; hg19: chr16-48209223;