16-16190408-T-C

Variant names:

• chr16-16190408-T-C
• rs2239322
• NM_001171.6:c.1432-41A>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.1432-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,607,170 control chromosomes in the GnomAD database, including 82,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6067 hom., cov: 31)
  • Exomes 𝑓: 0.31 (76555 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.21
• Publications: 11 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=-0.92).
• BP6: Variant 16-16190408-T-C is Benign according to our data. Variant chr16-16190408-T-C is described in ClinVar as Benign. ClinVar VariationId is 1257345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.1432-41A>G		intron_variant	Intron 11 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.1432-41A>G		intron_variant	Intron 11 of 30	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.1432-41A>G		intron_variant	Intron 11 of 28	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.1432-41A>G		intron_variant	Intron 11 of 31	5		ENSP00000483331.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38527 AN: 151914 Hom.: 6065 Cov.: 31

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.338 AC: 84098 AN: 248514 AF XY: 0.348

Gnomad AFR exome AF: 0.0881

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.315 AC: 458009 AN: 1455138 Hom.: 76555 Cov.: 32 AF XY: 0.321 AC XY: 232810 AN XY: 724252

African (AFR) AF: 0.0800 AC: 2669 AN: 33342

American (AMR) AF: 0.340 AC: 15174 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7378 AN: 26094

East Asian (EAS) AF: 0.463 AC: 18372 AN: 39660

South Asian (SAS) AF: 0.531 AC: 45672 AN: 86092

European-Finnish (FIN) AF: 0.360 AC: 18929 AN: 52636

Middle Eastern (MID) AF: 0.359 AC: 2018 AN: 5626

European-Non Finnish (NFE) AF: 0.297 AC: 328307 AN: 1106894

Other (OTH) AF: 0.324 AC: 19490 AN: 60178

GnomAD4 genome AF: 0.253 AC: 38533 AN: 152032 Hom.: 6067 Cov.: 31 AF XY: 0.264 AC XY: 19621 AN XY: 74322

African (AFR) AF: 0.0906 AC: 3758 AN: 41498

American (AMR) AF: 0.287 AC: 4386 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3468

East Asian (EAS) AF: 0.503 AC: 2580 AN: 5130

South Asian (SAS) AF: 0.534 AC: 2573 AN: 4822

European-Finnish (FIN) AF: 0.358 AC: 3786 AN: 10590

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19656 AN: 67946

Other (OTH) AF: 0.256 AC: 538 AN: 2104

Alfa AF: 0.288 Hom.: 3674

Bravo AF: 0.239

Asia WGS AF: 0.484 AC: 1680 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

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

Pseudoxanthoma elasticum, forme fruste Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.36
DANN	Benign	0.16
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2239322; hg19: chr16-16284265; COSMIC: COSV52741153;