16-16177541-A-T

Variant names:

• chr16-16177541-A-T
• NM_001171.6:c.2501T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001171.6(ABCC6):​c.2501T>A​(p.Met834Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.952

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 3 ACMG points.

• PM1: In a domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38016495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2501T>A	p.Met834Lys	missense_variant	Exon 19 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.2159T>A	p.Met720Lys	missense_variant	Exon 19 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.2452+1257T>A		intron_variant	Intron 18 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2501T>A	p.Met834Lys	missense_variant	Exon 19 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000622290.5	n.2501T>A		non_coding_transcript_exon_variant	Exon 19 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.2415+1257T>A		intron_variant	Intron 18 of 28	2		ENSP00000405002.2
ABCC6	ENST00000576683.1	n.-20T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.33	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.28
Sift	Benign	0.064	T
Sift4G	Benign	0.46	T
Polyphen		0.48	P
Vest4		0.46
MutPred		0.46		Gain of ubiquitination at M834 (P = 0.0162);
MVP		0.46
MPC		0.10
ClinPred		0.19	T
GERP RS		1.3
Varity_R		0.69
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-16271398;