rs72653762

Variant names:

• chr16-16202006-T-C
• rs72653762
• NM_001171.6:c.1171A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

The NM_001171.6(ABCC6):​c.1171A>G​(p.Arg391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,613,982 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (53 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:11 B:2
• Conservation: PhyloP100: 0.705
• Publications: 31 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet
• inherited pseudoxanthoma elasticum

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.080948204).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00471 (718/152334) while in subpopulation NFE AF = 0.00791 (538/68038). AF 95% confidence interval is 0.00735. There are 4 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.1171A>G	p.Arg391Gly	missense	Exon 9 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1171A>G	p.Arg391Gly	missense	Exon 9 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1171A>G	p.Arg391Gly	missense	Exon 9 of 30	NP_001427239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.1171A>G	p.Arg391Gly	missense	Exon 9 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.1171A>G	p.Arg391Gly	missense	Exon 9 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.1171A>G	p.Arg391Gly	missense	Exon 9 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152216 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00557 AC: 1397 AN: 250940 AF XY: 0.00574

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00704 AC: 10284 AN: 1461648 Hom.: 53 Cov.: 32 AF XY: 0.00695 AC XY: 5052 AN XY: 727134

African (AFR) AF: 0.00120 AC: 40 AN: 33472

American (AMR) AF: 0.00302 AC: 135 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00828 AC: 714 AN: 86248

European-Finnish (FIN) AF: 0.00504 AC: 269 AN: 53420

Middle Eastern (MID) AF: 0.00885 AC: 51 AN: 5762

European-Non Finnish (NFE) AF: 0.00776 AC: 8626 AN: 1111820

Other (OTH) AF: 0.00730 AC: 441 AN: 60378

GnomAD4 genome AF: 0.00471 AC: 718 AN: 152334 Hom.: 4 Cov.: 31 AF XY: 0.00432 AC XY: 322 AN XY: 74484

African (AFR) AF: 0.00113 AC: 47 AN: 41582

American (AMR) AF: 0.00288 AC: 44 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00791 AC: 538 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00688 Hom.: 1

Bravo AF: 0.00479

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00608 AC: 738

EpiCase AF: 0.00780

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	2	not provided (5)
-	3	-	Autosomal recessive inherited pseudoxanthoma elasticum (3)
-	2	-	not specified (2)
1	-	-	ABCC6-related disorder (1)
-	1	-	Arterial calcification, generalized, of infancy, 2 (1)
-	1	-	Pseudoxanthoma elasticum, forme fruste (1)
-	1	-	Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2;CN032334:Autosomal recessive inherited pseudoxanthoma elasticum (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.12
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.70
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.88
MPC		0.31
ClinPred		0.063	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.68
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs72653762; hg19: chr16-16295863;