rs63750125

Positions:

• chr16-16159541-G-C
• chr16-16159541-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001171.6(ABCC6):​c.3676C>G​(p.Leu1226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. L1226I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.932

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 4 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, 4 uncertain in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16159541-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.19873655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3676C>G	p.Leu1226Val	missense_variant	26/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3334C>G	p.Leu1112Val	missense_variant	26/31
ABCC6	NR_147784.1	n.3338C>G		non_coding_transcript_exon_variant	24/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3676C>G	p.Leu1226Val	missense_variant	26/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.3676C>G	p.Leu1226Val	missense_variant, NMD_transcript_variant	26/32	5
ABCC6	ENST00000456970.6	c.*685C>G		3_prime_UTR_variant, NMD_transcript_variant	24/29	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.44	T;.
Sift4G	Benign	0.41	T;.
Polyphen		0.33	B;.
Vest4		0.40
MutPred		0.58		Gain of MoRF binding (P = 0.09);.;
MVP		0.74
MPC		0.10
ClinPred		0.34	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.58

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: rs63750125; hg19: chr16-16253398;