rs59757815

Variant names:

• chr16-16182484-T-A
• rs59757815
• NM_001171.6:c.2175A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-16182484-T-A
• chr16-16182484-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171.6(ABCC6):​c.2175A>T​(p.Val725Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,614,148 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (81 hom., cov: 32)
  • Exomes 𝑓: 0.016 (339 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.263
• Publications: 5 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, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-16182484-T-A is Benign according to our data. Variant chr16-16182484-T-A is described in ClinVar as Benign. ClinVar VariationId is 433262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 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.2175A>T	p.Val725Val	synonymous	Exon 17 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.2175A>T	p.Val725Val	synonymous	Exon 17 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.2175A>T	p.Val725Val	synonymous	Exon 17 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.2175A>T	p.Val725Val	synonymous	Exon 17 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.2175A>T	p.Val725Val	synonymous	Exon 17 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.2175A>T	p.Val725Val	synonymous	Exon 17 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3772 AN: 152168 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0163 AC: 4107 AN: 251452 AF XY: 0.0172

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0162 AC: 23691 AN: 1461862 Hom.: 339 Cov.: 33 AF XY: 0.0168 AC XY: 12227 AN XY: 727228

African (AFR) AF: 0.0569 AC: 1904 AN: 33476

American (AMR) AF: 0.00890 AC: 398 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 390 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0378 AC: 3263 AN: 86252

European-Finnish (FIN) AF: 0.00135 AC: 72 AN: 53420

Middle Eastern (MID) AF: 0.0454 AC: 262 AN: 5768

European-Non Finnish (NFE) AF: 0.0146 AC: 16233 AN: 1111994

Other (OTH) AF: 0.0193 AC: 1163 AN: 60396

GnomAD4 genome AF: 0.0248 AC: 3778 AN: 152286 Hom.: 81 Cov.: 32 AF XY: 0.0239 AC XY: 1779 AN XY: 74458

African (AFR) AF: 0.0542 AC: 2250 AN: 41550

American (AMR) AF: 0.0183 AC: 280 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 941 AN: 68028

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0157 Hom.: 17

Bravo AF: 0.0268

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0180

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)
-	-	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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.11
DANN	Benign	0.58
PhyloP100		-0.26
Mutation Taster		=100/0	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: rs59757815; hg19: chr16-16276341;