16-16197959-G-C

Variant names:

• chr16-16197959-G-C
• rs58394656
• NM_001171.6:c.1338+62C>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+62C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,519,816 control chromosomes in the GnomAD database, including 63,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4632 hom., cov: 23)
  • Exomes 𝑓: 0.29 (59096 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.612
• Publications: 6 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=-0.9).
• BP6: Variant 16-16197959-G-C is Benign according to our data. Variant chr16-16197959-G-C is described in ClinVar as Benign. ClinVar VariationId is 1691106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 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+62C>G		intron	N/A	NP_001162.5
	ABCC6	NM_001440309.1		c.1338+62C>G		intron	N/A	NP_001427238.1
	ABCC6	NM_001440310.1		c.1338+62C>G		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+62C>G		intron	N/A	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.1338+62C>G		intron	N/A	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.1338+62C>G		intron	N/A	ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34098 AN: 147776 Hom.: 4637 Cov.: 23

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.288 AC: 395455 AN: 1371940 Hom.: 59096 AF XY: 0.287 AC XY: 195304 AN XY: 679626

African (AFR) AF: 0.102 AC: 3233 AN: 31712

American (AMR) AF: 0.157 AC: 5832 AN: 37130

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8600 AN: 25040

East Asian (EAS) AF: 0.122 AC: 4508 AN: 36808

South Asian (SAS) AF: 0.205 AC: 16294 AN: 79530

European-Finnish (FIN) AF: 0.250 AC: 11975 AN: 47918

Middle Eastern (MID) AF: 0.295 AC: 1524 AN: 5160

European-Non Finnish (NFE) AF: 0.311 AC: 327496 AN: 1051616

Other (OTH) AF: 0.280 AC: 15993 AN: 57026

GnomAD4 genome AF: 0.230 AC: 34083 AN: 147876 Hom.: 4632 Cov.: 23 AF XY: 0.227 AC XY: 16336 AN XY: 71970

African (AFR) AF: 0.105 AC: 4234 AN: 40256

American (AMR) AF: 0.223 AC: 3294 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1185 AN: 3434

East Asian (EAS) AF: 0.0956 AC: 466 AN: 4872

South Asian (SAS) AF: 0.202 AC: 916 AN: 4544

European-Finnish (FIN) AF: 0.249 AC: 2522 AN: 10118

Middle Eastern (MID) AF: 0.239 AC: 68 AN: 284

European-Non Finnish (NFE) AF: 0.308 AC: 20521 AN: 66666

Other (OTH) AF: 0.252 AC: 510 AN: 2022

Alfa AF: 0.136 Hom.: 260

Bravo AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pseudoxanthoma elasticum, forme fruste Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs58394656; hg19: chr16-16291816; COSMIC: COSV52746711; COSMIC: COSV52746711;