rs527236053

Variant names:

• chr16-16208729-T-C
• rs72657698
• NM_001171.6:c.793A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-16208729-T-C
• chrNT_187607.1-1866727-T-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.793A>G​(p.Arg265Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 151,816 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.067 (358 hom., cov: 30)
  • Exomes 𝑓: 0.037 (3822 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense, splice_region
• Scores: Splicing: ADA: 0.008483
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0140
• Publications: 14 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

ENSG00000305554 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022835135).
• BP6: Variant 16-16208729-T-C is Benign according to our data. Variant chr16-16208729-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0784 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.793A>G	p.Arg265Gly	missense splice_region	Exon 7 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.793A>G	p.Arg265Gly	missense splice_region	Exon 7 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.793A>G	p.Arg265Gly	missense splice_region	Exon 7 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.793A>G	p.Arg265Gly	missense splice_region	Exon 7 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.793A>G	p.Arg265Gly	missense splice_region	Exon 7 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.793A>G	p.Arg265Gly	missense splice_region	Exon 7 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10110 AN: 151698 Hom.: 359 Cov.: 30

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0802

Gnomad OTH AF: 0.0685

GnomAD2 exomes AF: 0.0427 AC: 10355 AN: 242738 AF XY: 0.0431

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.0231

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0603

Gnomad OTH exome AF: 0.0465

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0366 AC: 49797 AN: 1360146 Hom.: 3822 Cov.: 33 AF XY: 0.0372 AC XY: 25224 AN XY: 678628

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

African (AFR) AF: 0.0333 AC: 1060 AN: 31870

American (AMR) AF: 0.0269 AC: 1175 AN: 43648

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 1242 AN: 24788

East Asian (EAS) AF: 0.0427 AC: 1682 AN: 39386

South Asian (SAS) AF: 0.0199 AC: 1688 AN: 84616

European-Finnish (FIN) AF: 0.0479 AC: 2542 AN: 53016

Middle Eastern (MID) AF: 0.0410 AC: 224 AN: 5458

European-Non Finnish (NFE) AF: 0.0371 AC: 37847 AN: 1020230

Other (OTH) AF: 0.0409 AC: 2337 AN: 57134

⚠️ 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: 0.0666 AC: 10108 AN: 151816 Hom.: 358 Cov.: 30 AF XY: 0.0644 AC XY: 4777 AN XY: 74192

African (AFR) AF: 0.0598 AC: 2474 AN: 41398

American (AMR) AF: 0.0600 AC: 913 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.0330 AC: 170 AN: 5148

South Asian (SAS) AF: 0.0262 AC: 126 AN: 4808

European-Finnish (FIN) AF: 0.0448 AC: 474 AN: 10588

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0802 AC: 5442 AN: 67868

Other (OTH) AF: 0.0678 AC: 143 AN: 2110

Alfa AF: 0.0724 Hom.: 217

Bravo AF: 0.0681

ExAC AF: 0.0600 AC: 7282

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive inherited pseudoxanthoma elasticum (3)
-	-	3	not specified (3)
-	-	1	Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Inborn genetic diseases (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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.9
DANN	Benign	0.74
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.014
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.082
Sift	Benign	0.48	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.085
ClinPred		0.0025	T
GERP RS		-1.0
Varity_R		0.055
gMVP		0.19
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0085
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72657698; hg19: chr16-16302586; COSMIC: COSV52741028;