rs56019914

Variant names:

• chr16-16219796-G-A
• rs56019914
• NM_001171.6:c.345+26C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001171.6(ABCC6):​c.345+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,456,484 control chromosomes in the GnomAD database, including 953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (108 hom., cov: 23)
  • Exomes 𝑓: 0.035 (845 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.150
• Publications: 2 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

ENSG00000305554 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 16-16219796-G-A is Benign according to our data. Variant chr16-16219796-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0349 (5186/148734) while in subpopulation AFR AF = 0.0457 (1834/40172). AF 95% confidence interval is 0.0439. There are 108 homozygotes in GnomAd4. There are 2421 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 108 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.345+26C>T		intron_variant	Intron 3 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.345+26C>T		intron_variant	Intron 3 of 30	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5173 AN: 148620 Hom.: 106 Cov.: 23

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.0157

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0177

Gnomad EAS AF: 0.00488

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0238 AC: 2100 AN: 88368 AF XY: 0.0232

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0345 AC: 45159 AN: 1307750 Hom.: 845 Cov.: 22 AF XY: 0.0337 AC XY: 21864 AN XY: 649432

African (AFR) AF: 0.0468 AC: 1378 AN: 29430

American (AMR) AF: 0.0168 AC: 596 AN: 35570

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 421 AN: 24648

East Asian (EAS) AF: 0.00697 AC: 246 AN: 35274

South Asian (SAS) AF: 0.0166 AC: 1279 AN: 77224

European-Finnish (FIN) AF: 0.0301 AC: 1465 AN: 48682

Middle Eastern (MID) AF: 0.0141 AC: 55 AN: 3890

European-Non Finnish (NFE) AF: 0.0380 AC: 37916 AN: 998212

Other (OTH) AF: 0.0329 AC: 1803 AN: 54820

GnomAD4 genome AF: 0.0349 AC: 5186 AN: 148734 Hom.: 108 Cov.: 23 AF XY: 0.0334 AC XY: 2421 AN XY: 72494

African (AFR) AF: 0.0457 AC: 1834 AN: 40172

American (AMR) AF: 0.0229 AC: 341 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 61 AN: 3448

East Asian (EAS) AF: 0.00489 AC: 24 AN: 4906

South Asian (SAS) AF: 0.0156 AC: 71 AN: 4544

European-Finnish (FIN) AF: 0.0303 AC: 314 AN: 10358

Middle Eastern (MID) AF: 0.0174 AC: 5 AN: 288

European-Non Finnish (NFE) AF: 0.0363 AC: 2438 AN: 67192

Other (OTH) AF: 0.0413 AC: 84 AN: 2032

Alfa AF: 0.0325 Hom.: 20

Bravo AF: 0.0355

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:1

Mar 01, 2021

PXE International

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.6
DANN	Benign	0.56
PhyloP100		-0.15
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: rs56019914; hg19: chr16-16313653;