rs199702708

Variant names:

• chr11-17461758-C-G
• NM_000352.6:c.647G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-17461758-C-G
• chr11-17461758-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000352.6(ABCC8):​c.647G>C​(p.Arg216Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 116) in uniprot entity ABCC8_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.647G>C	p.Arg216Pro	missense_variant	Exon 5 of 39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.647G>C	p.Arg216Pro	missense_variant	Exon 5 of 39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.0	.;M;M;M;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.3	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.028	.;.;D;D;.;.;.;.
Sift4G	Benign	0.066	.;.;T;T;.;.;.;.
Polyphen		0.99	.;.;D;.;.;.;.;.
Vest4		0.80, 0.80
MutPred		0.55		Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);
MVP		0.94
MPC		1.1
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17483305;