dbSNP rs58760581: ABCC6:c.4208+9G>A (chr16-16154619-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001171.6(ABCC6):c.4208+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,611,610 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 31)

Exomes 𝑓: 0.018 ( 329 hom. )

Consequence

ABCC6
NM_001171.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.37

Publications

4 publications found

Variant links:

Genes affected

ABCC6 (HGNC:57): (ATP binding cassette subfamily C member 6) 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). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]

ABCC6 Gene-Disease associations (from GenCC):

arterial calcification, generalized, of infancy, 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
autosomal recessive inherited pseudoxanthoma elasticum
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet
inherited pseudoxanthoma elasticum
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-16154619-C-T is Benign according to our data. Variant chr16-16154619-C-T is described in ClinVar as Benign. ClinVar VariationId is 433396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1850/152242) while in subpopulation SAS AF = 0.0415 (200/4820). AF 95% confidence interval is 0.0368. There are 18 homozygotes in GnomAd4. There are 900 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ABCC6	NM_001171.6	MANE Select	c.4208+9G>A	intron	N/A	NP_001162.5
ABCC6	NM_001440309.1		c.4175+9G>A	intron	N/A	NP_001427238.1
ABCC6	NM_001440310.1		c.4040+9G>A	intron	N/A	NP_001427239.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.4208+9G>A	intron	N/A	ENSP00000205557.7	O95255-1
ABCC6	ENST00000909083.1		c.4304+9G>A	intron	N/A	ENSP00000579142.1
ABCC6	ENST00000909090.1		c.4301+9G>A	intron	N/A	ENSP00000579149.1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1849

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0151

AC:

3735

AN:

246964

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00288

Gnomad AMR exome

AF:

0.00539

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.000438

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0178

AC:

25980

AN:

1459368

Hom.:

329

Cov.:

AF XY:

0.0186

AC XY:

13499

AN XY:

725936

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

33426

American (AMR)

AF:

0.00530

AC:

237

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

384

AN:

26128

East Asian (EAS)

AF:

0.000227

AC:

AN:

39698

South Asian (SAS)

AF:

0.0416

AC:

3586

AN:

86112

European-Finnish (FIN)

AF:

0.0108

AC:

569

AN:

52864

Middle Eastern (MID)

AF:

0.0353

AC:

151

AN:

4282

European-Non Finnish (NFE)

AF:

0.0179

AC:

19912

AN:

1111932

Other (OTH)

AF:

0.0173

AC:

1042

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1540

3080

4619

6159

7699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.0122

AC:

1850

AN:

152242

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

900

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41562

American (AMR)

AF:

0.00804

AC:

123

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000775

AC:

AN:

5162

South Asian (SAS)

AF:

0.0415

AC:

200

AN:

4820

European-Finnish (FIN)

AF:

0.0141

AC:

150

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1158

AN:

67998

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0142

Hom.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0197

EpiControl

AF:

0.0199

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive inherited pseudoxanthoma elasticum (2)

not specified (2)

Arterial calcification, generalized, of infancy, 2 (1)

Pseudoxanthoma elasticum, forme fruste (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.015

(source)

DANN

Benign

0.60

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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