rs58694313

Variant names:

• chr16-16157674-C-T
• rs58694313
• NM_001171.6:c.3871G>A
• ABCC6 p.Ala1291Thr

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):​c.3871G>A​(p.Ala1291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,614,016 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (162 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (154 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.269
• Publications: 8 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), Laboratory for Molecular Medicine, G2P, 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025525987).
• BP6: Variant 16-16157674-C-T is Benign according to our data. Variant chr16-16157674-C-T is described in ClinVar as Benign. ClinVar VariationId is 379215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0873 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.3871G>A	p.Ala1291Thr	missense	Exon 27 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3838G>A	p.Ala1280Thr	missense	Exon 27 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3703G>A	p.Ala1235Thr	missense	Exon 26 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.3871G>A	p.Ala1291Thr	missense	Exon 27 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.3967G>A	p.Ala1323Thr	missense	Exon 28 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.3964G>A	p.Ala1322Thr	missense	Exon 28 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3926 AN: 152042 Hom.: 159 Cov.: 31

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.00693 AC: 1739 AN: 251118 AF XY: 0.00506

Gnomad AFR exome AF: 0.0928

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00277 AC: 4049 AN: 1461856 Hom.: 154 Cov.: 32 AF XY: 0.00247 AC XY: 1797 AN XY: 727236

African (AFR) AF: 0.0940 AC: 3148 AN: 33480

American (AMR) AF: 0.00512 AC: 229 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1112000

Other (OTH) AF: 0.00646 AC: 390 AN: 60396

GnomAD4 genome AF: 0.0260 AC: 3955 AN: 152160 Hom.: 162 Cov.: 31 AF XY: 0.0251 AC XY: 1864 AN XY: 74404

African (AFR) AF: 0.0897 AC: 3721 AN: 41494

American (AMR) AF: 0.00995 AC: 152 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68000

Other (OTH) AF: 0.0194 AC: 41 AN: 2108

Alfa AF: 0.00685 Hom.: 78

Bravo AF: 0.0301

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal recessive inherited pseudoxanthoma elasticum (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Pseudoxanthoma elasticum, forme fruste (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.27
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Uncertain	0.026	D
Sift4G	Benign	0.067	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.56
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58694313;

hg19: chr16-16251531;