NM_001171.6:c.1171A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BS1 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:12 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: Benign. The variant received -8 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.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,SD 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	3	2	not provided (6)
-	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;