13-95083266-C-G

Variant names:

• chr13-95083266-C-G
• NM_005845.5:c.2560G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005845.5(ABCC4):​c.2560G>C​(p.Val854Leu) 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 1,461,674 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V854F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

Genes affected

ABCC4 (HGNC:55): (ATP binding cassette subfamily C member 4 (PEL blood group)) 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). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This family member plays a role in cellular detoxification as a pump for its substrate, organic anions. It may also function in prostaglandin-mediated cAMP signaling in ciliogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17716965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.2560G>C	p.Val854Leu	missense_variant	Exon 21 of 31	ENST00000645237.2	NP_005836.2
ABCC4	NM_001301829.2	c.2419G>C	p.Val807Leu	missense_variant	Exon 20 of 30		NP_001288758.1
ABCC4	XM_047430034.1	c.2431G>C	p.Val811Leu	missense_variant	Exon 21 of 31		XP_047285990.1
ABCC4	XM_047430035.1	c.2011G>C	p.Val671Leu	missense_variant	Exon 18 of 28		XP_047285991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.2560G>C	p.Val854Leu	missense_variant	Exon 21 of 31		NM_005845.5	ENSP00000494609.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727142

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.84	L;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	.;N;.
REVEL	Benign	0.27
Sift	Benign	0.051	.;T;.
Sift4G	Benign	0.17	.;T;.
Polyphen		0.0050	B;B;B
Vest4		0.44
MutPred		0.46		Loss of catalytic residue at V854 (P = 0.0407);Loss of catalytic residue at V854 (P = 0.0407);.;
MVP		0.49
MPC		0.24
ClinPred		0.17	T
GERP RS		0.39
Varity_R		0.13
gMVP		0.69

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: chr13-95735520;