rs72664283

Variant names:

• chr16-16202100-T-C
• rs72664283
• NM_001171.6:c.1077A>G
• ABCC6 p.Ser359Ser

Your query was ambiguous. Multiple possible variants found:

• chr16-16202100-T-C
• chr16-16202100-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001171.6(ABCC6):​c.1077A>G​(p.Ser359Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,610,970 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S359S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (74 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.32
• Publications: 5 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), Laboratory for Molecular Medicine, G2P, 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=-0.89).
• BP6: Variant 16-16202100-T-C is Benign according to our data. Variant chr16-16202100-T-C is described in ClinVar as Benign. ClinVar VariationId is 379234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2031/152224) while in subpopulation AFR AF = 0.0395 (1639/41494). AF 95% confidence interval is 0.0379. There are 38 homozygotes in GnomAd4. There are 1031 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.1077A>G	p.Ser359Ser	synonymous	Exon 9 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1077A>G	p.Ser359Ser	synonymous	Exon 9 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1077A>G	p.Ser359Ser	synonymous	Exon 9 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.1077A>G	p.Ser359Ser	synonymous	Exon 9 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.1077A>G	p.Ser359Ser	synonymous	Exon 9 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.1077A>G	p.Ser359Ser	synonymous	Exon 9 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2023 AN: 152108 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00559 AC: 1402 AN: 250716 AF XY: 0.00526

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00274 AC: 4001 AN: 1458746 Hom.: 74 Cov.: 32 AF XY: 0.00295 AC XY: 2142 AN XY: 725700

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

African (AFR) AF: 0.0298 AC: 976 AN: 32724

American (AMR) AF: 0.00513 AC: 229 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26110

East Asian (EAS) AF: 0.00277 AC: 110 AN: 39680

South Asian (SAS) AF: 0.0124 AC: 1064 AN: 85758

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53418

Middle Eastern (MID) AF: 0.00731 AC: 42 AN: 5748

European-Non Finnish (NFE) AF: 0.00112 AC: 1239 AN: 1110496

Other (OTH) AF: 0.00488 AC: 294 AN: 60194

⚠️ 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: 0.0133 AC: 2031 AN: 152224 Hom.: 38 Cov.: 31 AF XY: 0.0138 AC XY: 1031 AN XY: 74442

African (AFR) AF: 0.0395 AC: 1639 AN: 41494

American (AMR) AF: 0.00719 AC: 110 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5178

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4818

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68022

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00816 Hom.: 1

Bravo AF: 0.0150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.64
DANN	Benign	0.53
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72664283;

hg19: chr16-16295957;