rs2606921

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001171.6(ABCC6):c.473C>T(p.Ala158Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 149,362 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A158A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 20 hom., cov: 25)

Exomes 𝑓: 0.0014 ( 53 hom. )

Failed GnomAD Quality Control

Consequence

ABCC6
NM_001171.6 missense, splice_region

Scores

Splicing: ADA: 0.0001696

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.12

Publications

9 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCC6 links:

ENSG00000305554 (HGNC:):

ENSG00000305554 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14915383).

BP6

Variant 16-16219555-G-A is Benign according to our data. Variant chr16-16219555-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 433205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.473C>T	p.Ala158Val	missense_variant, splice_region_variant	Exon 4 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 link	c.473C>T	p.Ala158Val	missense_variant, splice_region_variant	Exon 4 of 31	1	NM_001171.6	ENSP00000205557.7		O95255-1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1606

AN:

149250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00763

Gnomad ASJ

AF:

0.00500

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00974

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.0107

GnomAD2 exomes

AF:

0.00121

AC:

213

AN:

176348

AF XY:

0.00125

show subpopulations

Gnomad AFR exome

AF:

0.00848

Gnomad AMR exome

AF:

0.000562

Gnomad ASJ exome

AF:

0.000465

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000768

Gnomad NFE exome

AF:

0.000981

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00145

AC:

2069

AN:

1431380

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1028

AN XY:

710286

show subpopulations

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

African (AFR)

AF:

0.00867

AC:

278

AN:

32080

American (AMR)

AF:

0.00128

AC:

AN:

42958

Ashkenazi Jewish (ASJ)

AF:

0.00248

AC:

AN:

25406

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39390

South Asian (SAS)

AF:

0.00213

AC:

174

AN:

81856

European-Finnish (FIN)

AF:

0.000998

AC:

AN:

51084

Middle Eastern (MID)

AF:

0.00544

AC:

AN:

4042

European-Non Finnish (NFE)

AF:

0.00115

AC:

1257

AN:

1095708

Other (OTH)

AF:

0.00284

AC:

167

AN:

58856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

264

528

791

1055

1319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0108

AC:

1607

AN:

149362

Hom.:

Cov.:

AF XY:

0.00989

AC XY:

722

AN XY:

73012

show subpopulations

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

African (AFR)

AF:

0.0236

AC:

943

AN:

39932

American (AMR)

AF:

0.00769

AC:

116

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.00500

AC:

AN:

3398

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00975

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.0208

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00607

AC:

408

AN:

67250

Other (OTH)

AF:

0.0106

AC:

AN:

2074

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

129

258

387

516

645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00794

Hom.:

ExAC

AF:

0.0000262

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28655553, 31589614, 16392638, 16086317) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCC6: BP4, BS1 -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:1

Feb 02, 2021

PXE International

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Benign:1

Sep 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;N

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.031

Sift

Benign

0.23

T;.

Sift4G

Benign

0.26

T;D

Polyphen

0.17

B;.

Vest4

0.20

MutPred

0.24

Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);

MVP

0.45

MPC

1.3

ClinPred

0.0098

GERP RS

3.4

Varity_R

0.034

gMVP

0.12

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.098

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over