rs72664282

Variant names:

• chr16-16212202-C-T
• rs72664282
• NM_001171.6:c.645G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171.6(ABCC6):​c.645G>A​(p.Thr215Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,003,146 control chromosomes in the GnomAD database, including 1,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (215 hom., cov: 21)
  • Exomes 𝑓: 0.052 (1466 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.419
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-16212202-C-T is Benign according to our data. Variant chr16-16212202-C-T is described in ClinVar as Benign. ClinVar VariationId is 433208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.419 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0657 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.645G>A	p.Thr215Thr	synonymous	Exon 6 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.645G>A	p.Thr215Thr	synonymous	Exon 6 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.645G>A	p.Thr215Thr	synonymous	Exon 6 of 30	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.645G>A	p.Thr215Thr	synonymous	Exon 6 of 31	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.645G>A	p.Thr215Thr	synonymous	Exon 6 of 11	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.645G>A		non_coding_transcript_exon	Exon 6 of 29	ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6136 AN: 140068 Hom.: 216 Cov.: 21

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0428

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0338

GnomAD2 exomes AF: 0.0401 AC: 6470 AN: 161180 AF XY: 0.0405

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0523 AC: 45140 AN: 863000 Hom.: 1466 Cov.: 12 AF XY: 0.0511 AC XY: 23043 AN XY: 451024

African (AFR) AF: 0.0109 AC: 219 AN: 20164

American (AMR) AF: 0.0205 AC: 841 AN: 41056

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 851 AN: 22046

East Asian (EAS) AF: 0.00 AC: 0 AN: 36100

South Asian (SAS) AF: 0.0124 AC: 903 AN: 72824

European-Finnish (FIN) AF: 0.0590 AC: 3085 AN: 52288

Middle Eastern (MID) AF: 0.00921 AC: 42 AN: 4562

European-Non Finnish (NFE) AF: 0.0652 AC: 37374 AN: 573618

Other (OTH) AF: 0.0452 AC: 1825 AN: 40342

GnomAD4 genome AF: 0.0438 AC: 6135 AN: 140146 Hom.: 215 Cov.: 21 AF XY: 0.0411 AC XY: 2785 AN XY: 67786

African (AFR) AF: 0.0123 AC: 437 AN: 35648

American (AMR) AF: 0.0258 AC: 361 AN: 13966

Ashkenazi Jewish (ASJ) AF: 0.0428 AC: 143 AN: 3338

East Asian (EAS) AF: 0.000209 AC: 1 AN: 4776

South Asian (SAS) AF: 0.0113 AC: 50 AN: 4408

European-Finnish (FIN) AF: 0.0593 AC: 574 AN: 9684

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.0673 AC: 4394 AN: 65258

Other (OTH) AF: 0.0334 AC: 64 AN: 1914

Alfa AF: 0.0504 Hom.: 34

Bravo AF: 0.0379

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 31, 2019

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Mar 01, 2021

PXE International

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.4
DANN	Benign	0.54
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs72664282; hg19: chr16-16306059;