rs1555520951

Variant names:

• chr16-16212173-G-A
• rs1555520951
• NM_001171.6:c.662+12C>T

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.662+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 137,152 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 23)
  • Exomes 𝑓: 0.024 (314 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.564
• Publications: 0 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

ENSG00000305554 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-16212173-G-A is Benign according to our data. Variant chr16-16212173-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 433376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 43 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.662+12C>T		intron	N/A	NP_001162.5
	ABCC6	NM_001440309.1		c.662+12C>T		intron	N/A	NP_001427238.1
	ABCC6	NM_001440310.1		c.662+12C>T		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.662+12C>T		intron	N/A	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.662+12C>T		intron	N/A	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.662+12C>T		intron	N/A	ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2510 AN: 137078 Hom.: 43 Cov.: 23

Gnomad AFR AF: 0.00387

Gnomad AMI AF: 0.0139

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0172

Gnomad EAS AF: 0.00302

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00987

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.0166 AC: 2389 AN: 143728 AF XY: 0.0168

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00117

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0244 AC: 16526 AN: 678232 Hom.: 314 Cov.: 9 AF XY: 0.0241 AC XY: 8707 AN XY: 361336

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

African (AFR) AF: 0.00527 AC: 92 AN: 17460

American (AMR) AF: 0.0123 AC: 460 AN: 37496

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 411 AN: 20614

East Asian (EAS) AF: 0.00616 AC: 210 AN: 34068

South Asian (SAS) AF: 0.0166 AC: 1113 AN: 67112

European-Finnish (FIN) AF: 0.0243 AC: 1222 AN: 50338

Middle Eastern (MID) AF: 0.0131 AC: 49 AN: 3732

European-Non Finnish (NFE) AF: 0.0294 AC: 12130 AN: 413016

Other (OTH) AF: 0.0244 AC: 839 AN: 34396

⚠️ 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: 0.0183 AC: 2513 AN: 137152 Hom.: 43 Cov.: 23 AF XY: 0.0169 AC XY: 1120 AN XY: 66356

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

African (AFR) AF: 0.00386 AC: 131 AN: 33964

American (AMR) AF: 0.0156 AC: 215 AN: 13762

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 57 AN: 3308

East Asian (EAS) AF: 0.00303 AC: 14 AN: 4626

South Asian (SAS) AF: 0.00994 AC: 43 AN: 4324

European-Finnish (FIN) AF: 0.0179 AC: 176 AN: 9816

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.0284 AC: 1825 AN: 64332

Other (OTH) AF: 0.0203 AC: 38 AN: 1872

⚠️ 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: 0.0265 Hom.: 19

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive inherited pseudoxanthoma elasticum (1)
-	-	1	Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.62
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555520951; hg19: chr16-16306030;