rs9940825

Variant names:

• chr16-16198114-C-T
• rs9940825
• NM_001171.6:c.1245G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-16198114-C-T
• chr16-16198114-C-A

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.1245G>A​(p.Val415Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,611,634 control chromosomes in the GnomAD database, including 87,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7118 hom., cov: 33)
  • Exomes 𝑓: 0.33 (80315 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.804
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-16198114-C-T is Benign according to our data. Variant chr16-16198114-C-T is described in ClinVar as Benign. ClinVar VariationId is 433228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.804 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 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.1245G>A	p.Val415Val	synonymous	Exon 10 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1245G>A	p.Val415Val	synonymous	Exon 10 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1245G>A	p.Val415Val	synonymous	Exon 10 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.1245G>A	p.Val415Val	synonymous	Exon 10 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.1245G>A	p.Val415Val	synonymous	Exon 10 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.1245G>A	p.Val415Val	synonymous	Exon 10 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45196 AN: 152046 Hom.: 7122 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.285 AC: 70039 AN: 245644 AF XY: 0.286

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0947

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.326 AC: 475529 AN: 1459470 Hom.: 80315 Cov.: 51 AF XY: 0.323 AC XY: 234251 AN XY: 725842

African (AFR) AF: 0.249 AC: 8332 AN: 33462

American (AMR) AF: 0.269 AC: 11945 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5803 AN: 26070

East Asian (EAS) AF: 0.0903 AC: 3580 AN: 39646

South Asian (SAS) AF: 0.219 AC: 18836 AN: 85850

European-Finnish (FIN) AF: 0.314 AC: 16681 AN: 53208

Middle Eastern (MID) AF: 0.293 AC: 1691 AN: 5764

European-Non Finnish (NFE) AF: 0.352 AC: 390803 AN: 1110788

Other (OTH) AF: 0.296 AC: 17858 AN: 60278

GnomAD4 genome AF: 0.297 AC: 45189 AN: 152164 Hom.: 7118 Cov.: 33 AF XY: 0.291 AC XY: 21661 AN XY: 74398

African (AFR) AF: 0.253 AC: 10507 AN: 41522

American (AMR) AF: 0.294 AC: 4502 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 775 AN: 3472

East Asian (EAS) AF: 0.0959 AC: 495 AN: 5160

South Asian (SAS) AF: 0.207 AC: 997 AN: 4822

European-Finnish (FIN) AF: 0.310 AC: 3283 AN: 10600

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23578 AN: 67976

Other (OTH) AF: 0.302 AC: 638 AN: 2116

Alfa AF: 0.319 Hom.: 16123

Bravo AF: 0.294

Asia WGS AF: 0.148 AC: 513 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)
-	-	1	Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2;CN032334:Autosomal recessive inherited pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.47
PhyloP100		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9940825; hg19: chr16-16291971; COSMIC: COSV52741162; COSMIC: COSV52741162;