16-48170185-C-T

Variant names:

• chr16-48170185-C-T
• rs749983411
• NM_001370497.1:c.3811G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001370497.1(ABCC11):​c.3811G>A​(p.Val1271Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1271L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ABCC11 NM_001370497.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.39
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370497.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC11	NM_001370497.1	MANE Select	c.3811G>A	p.Val1271Met	missense	Exon 28 of 30	NP_001357426.1	Q96J66-1
	ABCC11	NM_001370496.1		c.3817G>A	p.Val1273Met	missense	Exon 28 of 30	NP_001357425.1
	ABCC11	NM_032583.4		c.3811G>A	p.Val1271Met	missense	Exon 29 of 31	NP_115972.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC11	ENST00000356608.7	TSL:1 MANE Select	c.3811G>A	p.Val1271Met	missense	Exon 28 of 30	ENSP00000349017.2	Q96J66-1
	ABCC11	ENST00000394747.5	TSL:1	c.3811G>A	p.Val1271Met	missense	Exon 27 of 29	ENSP00000378230.1	Q96J66-1
	ABCC11	ENST00000394748.5	TSL:1	c.3811G>A	p.Val1271Met	missense	Exon 28 of 30	ENSP00000378231.1	Q96J66-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.54		Gain of disorder (P = 0.116)
MVP		0.92
MPC		0.49
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.56
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749983411; hg19: chr16-48204096;