chr13-95163161-C-T

Position:

• chr13-95163161-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005845.5(ABCC4):​c.2269G>A​(p.Glu757Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,114 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.017 (583 hom.)
• Consequence: ABCC4 NM_005845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022514462).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC4	NM_005845.5	c.2269G>A	p.Glu757Lys	missense_variant	18/31	ENST00000645237.2	NP_005836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2	c.2269G>A	p.Glu757Lys	missense_variant	18/31		NM_005845.5	ENSP00000494609	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2041 AN: 152074 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0805

Gnomad SAS AF: 0.0492

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.0231 AC: 5796 AN: 251036 Hom.: 149 AF XY: 0.0233 AC XY: 3158 AN XY: 135676

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.0429

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0652

Gnomad SAS exome AF: 0.0521

Gnomad FIN exome AF: 0.00887

Gnomad NFE exome AF: 0.00984

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0167 AC: 24386 AN: 1460922 Hom.: 583 Cov.: 30 AF XY: 0.0176 AC XY: 12789 AN XY: 726784

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0504

Gnomad4 FIN exome AF: 0.00977

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0134 AC: 2041 AN: 152192 Hom.: 44 Cov.: 32 AF XY: 0.0144 AC XY: 1071 AN XY: 74414

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.0805

Gnomad4 SAS AF: 0.0492

Gnomad4 FIN AF: 0.00839

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0116 Hom.: 35

Bravo AF: 0.0141

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.0237 AC: 2874

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	3.8
DANN	Benign	0.47
DEOGEN2	Benign	0.25	T;T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.70	.;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	.;N;.;N;.
REVEL	Benign	0.26
Sift	Benign	0.34	.;T;.;T;.
Sift4G	Benign	0.46	.;T;.;T;T
Polyphen		0.0010	B;B;B;.;.
Vest4		0.043, 0.092
MPC		0.26
ClinPred		0.00044	T
GERP RS		1.4
Varity_R		0.058
gMVP		0.45

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: rs3765534; hg19: chr13-95815415; COSMIC: COSV65311705; COSMIC: COSV65311705;