NM_005845.5:c.912G>C

Variant names:

• chr13-95206781-C-G
• rs2274407
• NM_005845.5:c.912G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005845.5(ABCC4):​c.912G>C​(p.Lys304Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC4 NM_005845.5 missense, splice_region
• Scores: Splicing: ADA: 0.05551
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 67 publications found

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 Gene-Disease associations (from GenCC):

• qualitative platelet defect

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005845.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	NM_005845.5	MANE Select	c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 31	NP_005836.2	O15439-1
	ABCC4	NM_001301829.2		c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 30	NP_001288758.1	O15439-2
	ABCC4	NM_001105515.3		c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 21	NP_001098985.1	O15439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC4	ENST00000645237.2	MANE Select	c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 31	ENSP00000494609.1	O15439-1
	ABCC4	ENST00000629385.1	TSL:1	c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 21	ENSP00000487081.1	O15439-3
	ABCC4	ENST00000967420.1		c.912G>C	p.Lys304Asn	missense splice_region	Exon 8 of 31	ENSP00000637479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.044	D
Sift4G	Uncertain	0.042	D
Polyphen		0.086	B
Vest4		0.17
MutPred		0.18		Loss of MoRF binding (P = 0.0428)
MVP		0.76
MPC		0.30
ClinPred		0.40	T
GERP RS		1.7
Varity_R		0.14
gMVP		0.64
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.056
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2274407; hg19: chr13-95859035;