rs41278174

Variant names:

• chr16-16165739-G-A
• rs41278174
• NM_001171.6:c.3190C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.3190C>T​(p.Arg1064Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,760 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R1064Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 33)
  • Exomes 𝑓: 0.025 (553 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:16
• Conservation: PhyloP100: 3.53
• Publications: 27 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.010730177).
• BP6: Variant 16-16165739-G-A is Benign according to our data. Variant chr16-16165739-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 433305.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 = 0.0175 (2670/152336) while in subpopulation SAS AF = 0.0317 (153/4828). AF 95% confidence interval is 0.0276. There are 34 homozygotes in GnomAd4. There are 1358 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.3190C>T	p.Arg1064Trp	missense	Exon 23 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3157C>T	p.Arg1053Trp	missense	Exon 23 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3022C>T	p.Arg1008Trp	missense	Exon 22 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.3190C>T	p.Arg1064Trp	missense	Exon 23 of 31	ENSP00000205557.7
	ABCC6	ENST00000909083.1		c.3286C>T	p.Arg1096Trp	missense	Exon 24 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.3283C>T	p.Arg1095Trp	missense	Exon 24 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2669 AN: 152218 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0207 AC: 5197 AN: 251186 AF XY: 0.0216

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00867

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0248 AC: 36279 AN: 1461424 Hom.: 553 Cov.: 33 AF XY: 0.0250 AC XY: 18157 AN XY: 726986

African (AFR) AF: 0.00341 AC: 114 AN: 33480

American (AMR) AF: 0.00912 AC: 408 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 546 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0311 AC: 2683 AN: 86258

European-Finnish (FIN) AF: 0.0340 AC: 1803 AN: 52964

Middle Eastern (MID) AF: 0.0177 AC: 102 AN: 5768

European-Non Finnish (NFE) AF: 0.0262 AC: 29159 AN: 1112006

Other (OTH) AF: 0.0242 AC: 1460 AN: 60390

GnomAD4 genome AF: 0.0175 AC: 2670 AN: 152336 Hom.: 34 Cov.: 33 AF XY: 0.0182 AC XY: 1358 AN XY: 74478

African (AFR) AF: 0.00430 AC: 179 AN: 41580

American (AMR) AF: 0.00935 AC: 143 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4828

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0246 AC: 1674 AN: 68038

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0224 Hom.: 157

Bravo AF: 0.0148

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00410 AC: 18

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0205 AC: 2488

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	-	3	Autosomal recessive inherited pseudoxanthoma elasticum (4)
-	-	4	not specified (4)
-	-	2	Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 (2)
-	-	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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.5
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.25
MPC		0.38
ClinPred		0.041	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.55
Mutation Taster		=89/11	disease causing (ClinVar)

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: rs41278174; hg19: chr16-16259596; COSMIC: COSV52744032;