NM_001171.6:c.3883-24G>A

Variant names:

• chr16-16155055-C-T
• rs59513011
• NM_001171.6:c.3883-24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.3883-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,544,704 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (56 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.965
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-16155055-C-T is Benign according to our data. Variant chr16-16155055-C-T is described in ClinVar as Benign. ClinVar VariationId is 433418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00502 (765/152260) while in subpopulation SAS AF = 0.0114 (55/4820). AF 95% confidence interval is 0.009. There are 6 homozygotes in GnomAd4. There are 385 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.3883-24G>A		intron	N/A	NP_001162.5
	ABCC6	NM_001440309.1		c.3850-24G>A		intron	N/A	NP_001427238.1
	ABCC6	NM_001440310.1		c.3715-24G>A		intron	N/A	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.3883-24G>A		intron	N/A	ENSP00000205557.7
	ABCC6	ENST00000576204.6	TSL:5	n.722G>A		non_coding_transcript_exon	Exon 1 of 2
	ABCC6	ENST00000456970.6	TSL:2	n.*892-24G>A		intron	N/A	ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152142 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00604 AC: 892 AN: 147628 AF XY: 0.00668

Gnomad AFR exome AF: 0.000486

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.00868

Gnomad EAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00741

GnomAD4 exome AF: 0.00571 AC: 7945 AN: 1392444 Hom.: 56 Cov.: 32 AF XY: 0.00595 AC XY: 4083 AN XY: 686634

African (AFR) AF: 0.000949 AC: 30 AN: 31624

American (AMR) AF: 0.00428 AC: 153 AN: 35764

Ashkenazi Jewish (ASJ) AF: 0.00792 AC: 199 AN: 25142

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35760

South Asian (SAS) AF: 0.0126 AC: 1000 AN: 79248

European-Finnish (FIN) AF: 0.00218 AC: 95 AN: 43560

Middle Eastern (MID) AF: 0.0158 AC: 90 AN: 5690

European-Non Finnish (NFE) AF: 0.00556 AC: 5997 AN: 1077772

Other (OTH) AF: 0.00651 AC: 377 AN: 57884

GnomAD4 genome AF: 0.00502 AC: 765 AN: 152260 Hom.: 6 Cov.: 31 AF XY: 0.00517 AC XY: 385 AN XY: 74458

African (AFR) AF: 0.00101 AC: 42 AN: 41548

American (AMR) AF: 0.00667 AC: 102 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4820

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68004

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00523 Hom.: 2

Bravo AF: 0.00480

Asia WGS AF: 0.00866 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive inherited pseudoxanthoma elasticum (3)
-	-	3	not provided (3)
-	-	1	ABCC6-related disorder (1)
-	-	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	-0.82
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs59513011; hg19: chr16-16248912;