rs80356634

Positions:

• chr11-17474961-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_000352.6(ABCC8):​c.215A>G​(p.Asn72Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.26

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 19) in uniprot entity ABCC8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17474961-T-C is Pathogenic according to our data. Variant chr11-17474961-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9107.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.215A>G	p.Asn72Ser	missense_variant	2/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.215A>G	p.Asn72Ser	missense_variant	2/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Type 2 diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 13, 2023

- -

Diabetes mellitus, permanent neonatal 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Permanent neonatal diabetes mellitus Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T;.;.;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.4	.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	.;.;N;N;.;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.15	.;.;T;T;.;.;.;.
Sift4G	Benign	0.12	.;.;T;T;.;.;.;.
Polyphen		0.40	.;.;B;.;.;.;.;.
Vest4		0.78, 0.79
MutPred		0.80		Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);Gain of catalytic residue at G70 (P = 0.1195);
MVP		0.93
MPC		0.24
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.84

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: rs80356634; hg19: chr11-17496508;