16-16198014-G-C

Variant names:

• chr16-16198014-G-C
• rs9940089
• NM_001171.6:c.1338+7C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):​c.1338+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 1,612,304 control chromosomes in the GnomAD database, including 492,567 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43554 hom., cov: 28)
  • Exomes 𝑓: 0.78 (449013 hom.)
• Consequence: ABCC6 NM_001171.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002497
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.78
• Publications: 15 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 16-16198014-G-C is Benign according to our data. Variant chr16-16198014-G-C is described in ClinVar as Benign. ClinVar VariationId is 433382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.1338+7C>G		splice_region intron	N/A	NP_001162.5
	ABCC6	NM_001440309.1		c.1338+7C>G		splice_region intron	N/A	NP_001427238.1
	ABCC6	NM_001440310.1		c.1338+7C>G		splice_region intron	N/A	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.1338+7C>G		splice_region intron	N/A	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.1338+7C>G		splice_region intron	N/A	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.1338+7C>G		splice_region intron	N/A	ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114304 AN: 151348 Hom.: 43521 Cov.: 28

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.800 AC: 198381 AN: 248118 AF XY: 0.796

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.947

Gnomad FIN exome AF: 0.842

Gnomad NFE exome AF: 0.770

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.783 AC: 1143576 AN: 1460838 Hom.: 449013 Cov.: 50 AF XY: 0.783 AC XY: 568907 AN XY: 726730

African (AFR) AF: 0.680 AC: 22765 AN: 33458

American (AMR) AF: 0.864 AC: 38601 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 17559 AN: 26122

East Asian (EAS) AF: 0.931 AC: 36946 AN: 39690

South Asian (SAS) AF: 0.818 AC: 70480 AN: 86170

European-Finnish (FIN) AF: 0.844 AC: 45035 AN: 53360

Middle Eastern (MID) AF: 0.721 AC: 4159 AN: 5768

European-Non Finnish (NFE) AF: 0.775 AC: 861579 AN: 1111226

Other (OTH) AF: 0.770 AC: 46452 AN: 60360

GnomAD4 genome AF: 0.755 AC: 114386 AN: 151466 Hom.: 43554 Cov.: 28 AF XY: 0.759 AC XY: 56162 AN XY: 73950

African (AFR) AF: 0.680 AC: 28093 AN: 41286

American (AMR) AF: 0.788 AC: 12003 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2350 AN: 3466

East Asian (EAS) AF: 0.937 AC: 4753 AN: 5072

South Asian (SAS) AF: 0.814 AC: 3905 AN: 4800

European-Finnish (FIN) AF: 0.840 AC: 8803 AN: 10474

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.768 AC: 52127 AN: 67838

Other (OTH) AF: 0.744 AC: 1559 AN: 2096

Alfa AF: 0.743 Hom.: 10810

Bravo AF: 0.749

EpiCase AF: 0.754

EpiControl AF: 0.752

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Mar 01, 2021

PXE International

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Pseudoxanthoma elasticum, forme fruste Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arterial calcification, generalized, of infancy, 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.38
DANN	Benign	0.42
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs9940089; hg19: chr16-16291871;