chr16-16161567-G-A

Variant names:

• chr16-16161567-G-A
• rs41278172
• NM_001171.6:c.3507-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.3507-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,868 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.018 (326 hom.)
• Consequence: ABCC6 NM_001171.6 splice_region, intron
• Scores: Splicing: ADA: 0.02283
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.36
• Publications: 11 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-16161567-G-A is Benign according to our data. Variant chr16-16161567-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281169.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 = 0.0154 (2342/152296) while in subpopulation SAS AF = 0.0238 (115/4826). AF 95% confidence interval is 0.0203. There are 31 homozygotes in GnomAd4. There are 1200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,AD,SD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.3507-3C>T		splice_region intron	N/A	NP_001162.5
	ABCC6	NM_001440309.1		c.3474-3C>T		splice_region intron	N/A	NP_001427238.1
	ABCC6	NM_001440310.1		c.3339-3C>T		splice_region intron	N/A	NP_001427239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.3507-3C>T		splice_region intron	N/A	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.3603-3C>T		splice_region intron	N/A	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.3600-3C>T		splice_region intron	N/A	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2342 AN: 152178 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0164 AC: 4100 AN: 250166 AF XY: 0.0174

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.00868

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0181 AC: 26517 AN: 1461572 Hom.: 326 Cov.: 34 AF XY: 0.0184 AC XY: 13359 AN XY: 727062

African (AFR) AF: 0.00266 AC: 89 AN: 33480

American (AMR) AF: 0.00868 AC: 388 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 397 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0218 AC: 1882 AN: 86258

European-Finnish (FIN) AF: 0.0305 AC: 1621 AN: 53118

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 20998 AN: 1112000

Other (OTH) AF: 0.0173 AC: 1045 AN: 60392

GnomAD4 genome AF: 0.0154 AC: 2342 AN: 152296 Hom.: 31 Cov.: 32 AF XY: 0.0161 AC XY: 1200 AN XY: 74474

African (AFR) AF: 0.00354 AC: 147 AN: 41562

American (AMR) AF: 0.0121 AC: 185 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4826

European-Finnish (FIN) AF: 0.0368 AC: 391 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0207 AC: 1411 AN: 68014

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0175 Hom.: 52

Bravo AF: 0.0122

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0187

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Autosomal recessive inherited pseudoxanthoma elasticum (2)
-	-	1	Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Finnish congenital nephrotic syndrome (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	-0.42
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.023
dbscSNV1_RF	Benign	0.65
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: rs41278172; hg19: chr16-16255424;