16-16016542-T-C

Variant names:

• chr16-16016542-T-C
• rs1358279091
• NM_004996.4:c.536T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004996.4(ABCC1):​c.536T>C​(p.Phe179Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC1 NM_004996.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

ABCC1 (HGNC:51): (ATP binding cassette subfamily C member 1 (ABCC1 blood group)) 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 full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutatione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternatively spliced variants of this gene have been described but their full-length nature is unknown. [provided by RefSeq, Apr 2012]

ABCC1 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hearing loss, autosomal dominant 77

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004996.4. 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
	ABCC1	NM_004996.4	MANE Select	c.536T>C	p.Phe179Ser	missense	Exon 5 of 31	NP_004987.2	P33527-1
	ABCC1	NM_019902.2		c.536T>C	p.Phe179Ser	missense	Exon 5 of 30	NP_063957.2
	ABCC1	NM_019898.3		c.536T>C	p.Phe179Ser	missense	Exon 5 of 30	NP_063953.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC1	ENST00000399410.8	TSL:1 MANE Select	c.536T>C	p.Phe179Ser	missense	Exon 5 of 31	ENSP00000382342.3	P33527-1
	ABCC1	ENST00000572882.3	TSL:1	c.536T>C	p.Phe179Ser	missense	Exon 5 of 30	ENSP00000461615.2	P33527-2
	ABCC1	ENST00000574224.2	TSL:1	n.611T>C		non_coding_transcript_exon	Exon 5 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.097
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.044	D
Polyphen		0.0010	B
Vest4		0.51
MutPred		0.58		Loss of helix (P = 0.0444)
MVP		0.47
MPC		0.60
ClinPred		0.78	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.56

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

Other links and lift over

dbSNP: rs1358279091; hg19: chr16-16110399;