chr16-16187150-A-G

Variant names:

• chr16-16187150-A-G
• rs12931472
• NM_001171.6:c.1841T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):​c.1841T>C​(p.Val614Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,612,214 control chromosomes in the GnomAD database, including 183,537 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V614V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.44 (15257 hom., cov: 31)
  • Exomes 𝑓: 0.47 (168280 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.29
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.334803E-5).
• BP6: Variant 16-16187150-A-G is Benign according to our data. Variant chr16-16187150-A-G is described in ClinVar as Benign. ClinVar VariationId is 433244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.499 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.1841T>C	p.Val614Ala	missense	Exon 14 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1841T>C	p.Val614Ala	missense	Exon 14 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1841T>C	p.Val614Ala	missense	Exon 14 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.1841T>C	p.Val614Ala	missense	Exon 14 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.1841T>C	p.Val614Ala	missense	Exon 14 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.1841T>C	p.Val614Ala	missense	Exon 14 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66732 AN: 151770 Hom.: 15248 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.444

GnomAD2 exomes AF: 0.424 AC: 105779 AN: 249242 AF XY: 0.418

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.473 AC: 691156 AN: 1460326 Hom.: 168280 Cov.: 45 AF XY: 0.467 AC XY: 339017 AN XY: 726444

African (AFR) AF: 0.382 AC: 12783 AN: 33442

American (AMR) AF: 0.474 AC: 21114 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 11561 AN: 26120

East Asian (EAS) AF: 0.183 AC: 7264 AN: 39682

South Asian (SAS) AF: 0.268 AC: 23048 AN: 86150

European-Finnish (FIN) AF: 0.457 AC: 24340 AN: 53270

Middle Eastern (MID) AF: 0.355 AC: 2045 AN: 5756

European-Non Finnish (NFE) AF: 0.506 AC: 562297 AN: 1111010

Other (OTH) AF: 0.443 AC: 26704 AN: 60320

GnomAD4 genome AF: 0.440 AC: 66767 AN: 151888 Hom.: 15257 Cov.: 31 AF XY: 0.430 AC XY: 31916 AN XY: 74250

African (AFR) AF: 0.383 AC: 15844 AN: 41420

American (AMR) AF: 0.460 AC: 7022 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1527 AN: 3468

East Asian (EAS) AF: 0.151 AC: 781 AN: 5160

South Asian (SAS) AF: 0.254 AC: 1221 AN: 4808

European-Finnish (FIN) AF: 0.442 AC: 4655 AN: 10540

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.503 AC: 34162 AN: 67908

Other (OTH) AF: 0.439 AC: 926 AN: 2110

Alfa AF: 0.471 Hom.: 42466

Bravo AF: 0.443

TwinsUK AF: 0.505 AC: 1872

ALSPAC AF: 0.499 AC: 1924

ESP6500AA AF: 0.384 AC: 1687

ESP6500EA AF: 0.505 AC: 4342

ExAC AF: 0.421 AC: 51081

Asia WGS AF: 0.215 AC: 746 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive inherited pseudoxanthoma elasticum (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	0.056
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.3
DANN	Benign	0.49
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	0.000093	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.19
Sift	Benign	0.54	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.080
ClinPred		0.011	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.21
Mutation Taster		=94/6	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: rs12931472; hg19: chr16-16281007; COSMIC: COSV52741375;