13-95083230-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005845.5(ABCC4):c.2596A>G(p.Ile866Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,080 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (30 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.85

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009965599).
• BP6: Variant 13-95083230-T-C is Benign according to our data. Variant chr13-95083230-T-C is described in ClinVar as [Benign]. Clinvar id is 718083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC4	NM_005845.5	c.2596A>G	p.Ile866Val	missense_variant	21/31	ENST00000645237.2
ABCC4	NM_001301829.2	c.2455A>G	p.Ile819Val	missense_variant	20/30
ABCC4	XM_047430034.1	c.2467A>G	p.Ile823Val	missense_variant	21/31
ABCC4	XM_047430035.1	c.2047A>G	p.Ile683Val	missense_variant	18/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC4	ENST00000645237.2	c.2596A>G	p.Ile866Val	missense_variant	21/31		NM_005845.5	P1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152162 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00410 AC: 1031 AN: 251180 Hom.: 7 AF XY: 0.00424 AC XY: 575 AN XY: 135744

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00748

Gnomad NFE exome AF: 0.00723

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00501 AC: 7327 AN: 1461800 Hom.: 30 Cov.: 31 AF XY: 0.00492 AC XY: 3575 AN XY: 727200

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00728

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152280 Hom.: 5 Cov.: 32 AF XY: 0.00347 AC XY: 258 AN XY: 74458

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00895

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00517 Hom.: 2

Bravo AF: 0.00310

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00464 AC: 563

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00415

EpiControl AF: 0.00528

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	12
Dann	Uncertain	0.97
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Polyphen		0.0050	B;B;B
Vest4		0.15
MVP		0.51
MPC		0.21
ClinPred		0.0063	T
GERP RS		0.10
Varity_R		0.043
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

LitVar

Other links and lift over

dbSNP: rs139970608; hg19: chr13-95735484;