dbSNP rs2274407: ABCC4:p.Lys304Asn (chr13-95206781-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005845.5(ABCC4):c.912G>T(p.Lys304Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,613,542 control chromosomes in the GnomAD database, including 6,843 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.10 ( 1006 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5837 hom. )

Consequence

ABCC4
NM_005845.5 missense, splice_region

Scores

Splicing: ADA: 0.5090

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Variant links:

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]

ABCC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020405948).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC4	NM_005845.5 link	c.912G>T	p.Lys304Asn	missense_variant, splice_region_variant	Exon 8 of 31	ENST00000645237.2	NP_005836.2	O15439-1A8K2Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC4	ENST00000645237.2 link	c.912G>T	p.Lys304Asn	missense_variant, splice_region_variant	Exon 8 of 31		NM_005845.5	ENSP00000494609.1		O15439-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15803

AN:

152006

Hom.:

1004

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0812

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.176

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0631

Gnomad MID

AF:

0.121

Gnomad NFE

AF:

0.0682

Gnomad OTH

AF:

0.107

GnomAD3 exomes

AF:

0.0972

AC:

24412

AN:

251164

Hom.:

1369

AF XY:

0.0974

AC XY:

13228

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.0941

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.167

Gnomad SAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0613

Gnomad NFE exome

AF:

0.0698

Gnomad OTH exome

AF:

0.0944

GnomAD4 exome

AF:

0.0802

AC:

117262

AN:

1461418

Hom.:

5837

Cov.:

AF XY:

0.0820

AC XY:

59601

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.0919

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.219

Gnomad4 SAS exome

AF:

0.135

Gnomad4 FIN exome

AF:

0.0625

Gnomad4 NFE exome

AF:

0.0663

Gnomad4 OTH exome

AF:

0.0962

GnomAD4 genome

AF:

0.104

AC:

15809

AN:

152124

Hom.:

1006

Cov.:

AF XY:

0.102

AC XY:

7568

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.0810

Gnomad4 ASJ

AF:

0.132

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.144

Gnomad4 FIN

AF:

0.0631

Gnomad4 NFE

AF:

0.0683

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.0791

Hom.:

843

Bravo

AF:

0.108

TwinsUK

AF:

0.0615

AC:

228

ALSPAC

AF:

0.0711

AC:

274

ESP6500AA

AF:

0.171

AC:

754

ESP6500EA

AF:

0.0705

AC:

606

ExAC

AF:

0.100

AC:

12165

Asia WGS

AF:

0.179

AC:

626

AN:

3478

EpiCase

AF:

0.0718

EpiControl

AF:

0.0736

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T;.;.;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

.;D;D;D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.0020

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;.;L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

.;N;.;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.044

.;D;.;T;.;.

Sift4G

Uncertain

0.042

.;D;.;D;D;.

Polyphen

0.086

B;B;B;.;.;.

Vest4

0.17, 0.19, 0.15

MutPred

0.18

Loss of MoRF binding (P = 0.0428);Loss of MoRF binding (P = 0.0428);Loss of MoRF binding (P = 0.0428);.;Loss of MoRF binding (P = 0.0428);.;

MPC

0.30

ClinPred

0.021

GERP RS

1.7

Varity_R

0.14

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.51

dbscSNV1_RF

Benign

0.38

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over