Genetic Variant ABCC1:p.Pro669Pro (chr16-16079370-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BS1BS2

The NM_004996.4(ABCC1):c.2007C>T(p.Pro669Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,996 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P669P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 24 hom. )

Consequence

ABCC1
NM_004996.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.70

Publications

10 publications found

Variant links:

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)

ABCC1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004996.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP7

Synonymous conserved (PhyloP=-3.7 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00114 (174/152286) while in subpopulation EAS AF = 0.0232 (120/5182). AF 95% confidence interval is 0.0198. There are 3 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 174 Unknown,AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCC1	NM_004996.4	MANE Select	c.2007C>T	p.Pro669Pro	synonymous	Exon 16 of 31	NP_004987.2	P33527-1
ABCC1	NM_019901.2		c.1881C>T	p.Pro627Pro	synonymous	Exon 15 of 30	NP_063956.2
ABCC1	NM_019902.2		c.1860C>T	p.Pro620Pro	synonymous	Exon 15 of 30	NP_063957.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCC1	ENST00000399410.8	TSL:1 MANE Select	c.2007C>T	p.Pro669Pro	synonymous	Exon 16 of 31	ENSP00000382342.3	P33527-1
ABCC1	ENST00000572882.3	TSL:1	c.2007C>T	p.Pro669Pro	synonymous	Exon 16 of 30	ENSP00000461615.2	P33527-2
ABCC1	ENST00000914156.1		c.2163C>T	p.Pro721Pro	synonymous	Exon 17 of 32	ENSP00000584215.1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0231

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00222

AC:

554

AN:

249254

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.0242

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000990

GnomAD4 exome

AF:

0.00117

AC:

1713

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

909

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.0318

AC:

1263

AN:

39700

South Asian (SAS)

AF:

0.00279

AC:

241

AN:

86252

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1111886

Other (OTH)

AF:

0.000944

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

183

275

366

458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00114

AC:

174

AN:

152286

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0232

AC:

120

AN:

5182

South Asian (SAS)

AF:

0.00415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00513

Hom.:

710

Bravo

AF:

0.00128

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.1

(source)

DANN

Benign

0.51

PhyloP100

-3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over