rs72657699

Variant names:

• chr16-16203453-T-C
• rs72657699
• NM_001171.6:c.955A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001171.6(ABCC6):​c.955A>G​(p.Ile319Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,760 control chromosomes in the GnomAD database, including 20 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (12 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.36
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003887266).
• BP6: Variant 16-16203453-T-C is Benign according to our data. Variant chr16-16203453-T-C is described in ClinVar as Benign. ClinVar VariationId is 388992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.955A>G	p.Ile319Val	missense	Exon 8 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.955A>G	p.Ile319Val	missense	Exon 8 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.955A>G	p.Ile319Val	missense	Exon 8 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.955A>G	p.Ile319Val	missense	Exon 8 of 31	ENSP00000205557.7
	ABCC6	ENST00000909083.1		c.955A>G	p.Ile319Val	missense	Exon 8 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.955A>G	p.Ile319Val	missense	Exon 8 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1065 AN: 151980 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00127 AC: 318 AN: 250582 AF XY: 0.00111

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1460664 Hom.: 12 Cov.: 32 AF XY: 0.000402 AC XY: 292 AN XY: 726782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0108 AC: 353 AN: 32748

American (AMR) AF: 0.000806 AC: 36 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00278 AC: 110 AN: 39594

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86242

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111798

Other (OTH) AF: 0.000978 AC: 59 AN: 60298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00701 AC: 1066 AN: 152096 Hom.: 8 Cov.: 32 AF XY: 0.00699 AC XY: 520 AN XY: 74378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0235 AC: 973 AN: 41374

American (AMR) AF: 0.00359 AC: 55 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00464 AC: 24 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00334 Hom.: 0

ExAC AF: 0.00189 AC: 229

ClinVar

ClinVar submissions as Germline

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	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.012
DANN	Benign	0.49
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.84	N
PhyloP100		-1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.21
Sift	Benign	0.96	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.025
MVP		0.44
MPC		0.058
ClinPred		0.0028	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.23
Mutation Taster		=98/2	polymorphism

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: rs72657699; hg19: chr16-16297310;