11-17428382-C-G

Position:

• chr11-17428382-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000389817.8(ABCC8):​c.1947G>C​(p.Lys649Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K649K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC8 ENST00000389817.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

Genes affected

ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) 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 protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35491383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.1947G>C	p.Lys649Asn	missense_variant	14/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.1947G>C	p.Lys649Asn	missense_variant	14/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T;.;.;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	.;.;N;N;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	.;.;D;D;.;.;.;.
Sift4G	Benign	0.083	.;.;T;T;.;.;.;.
Polyphen		0.021	.;.;B;.;.;.;.;.
Vest4		0.66, 0.67
MutPred		0.30		.;Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);.;.;.;.;
MVP		0.70
MPC		0.83
ClinPred		0.96	D
GERP RS		2.2
Varity_R		0.32
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1799858; hg19: chr11-17449929;