rs1462269230

chr16-16150657-C-Achr16-16150657-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001171.6(ABCC6):c.4324G>T(p.Ala1442Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1442T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.857

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity MRP6_HUMAN there are 72 pathogenic changes around while only 8 benign (90%) in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.1122314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4324G>T	p.Ala1442Ser	missense_variant	30/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3982G>T	p.Ala1328Ser	missense_variant	30/31
ABCC6	NR_147784.1	n.3986G>T		non_coding_transcript_exon_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4324G>T	p.Ala1442Ser	missense_variant	30/31	1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*1333G>T		3_prime_UTR_variant, NMD_transcript_variant	28/29	2
ABCC6	ENST00000622290.5	c.*496G>T		3_prime_UTR_variant, NMD_transcript_variant	31/32	5

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248604 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461152 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	8.9
Dann	Benign	0.79
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.10	N;.
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.29	N;.
REVEL	Benign	0.12
Sift	Benign	0.95	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.089	B;.
Vest4		0.099
MutPred		0.48		Gain of disorder (P = 0.0521);.;
MVP		0.64
MPC		0.064
ClinPred		0.045	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1462269230; hg19: chr16-16244514;