11-17393742-C-G

Position:

• chr11-17393742-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000352.6(ABCC8):​c.4563G>C​(p.Lys1521Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409

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 4 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.4563G>C	p.Lys1521Asn	missense_variant	38/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.4563G>C	p.Lys1521Asn	missense_variant	38/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;.;T;.;.;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	.;.;N;N;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.34	.;.;T;T;.;.;.;.
Sift4G	Benign	0.36	.;.;T;T;.;.;.;.
Polyphen		0.45	.;.;B;.;.;.;.;.
Vest4		0.91, 0.93
MutPred		0.81		.;.;Loss of methylation at K1521 (P = 0.0127);.;.;.;Loss of methylation at K1521 (P = 0.0127);.;
MVP		0.81
MPC		0.85
ClinPred		0.82	D
GERP RS		3.2
Varity_R		0.25
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142272833; hg19: chr11-17415289;