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rs1554924035

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000352.6(ABCC8):โ€‹c.2202delโ€‹(p.Ala736LeufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: ๐‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes ๐‘“: 6.8e-7 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5O:2

Conservation

PhyloP100: -2.06
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-17427068-CT-C is Pathogenic according to our data. Variant chr11-17427068-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555310.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_risk_allele=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCC8NM_000352.6 linkuse as main transcriptc.2202del p.Ala736LeufsTer12 frameshift_variant 16/39 ENST00000389817.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCC8ENST00000389817.8 linkuse as main transcriptc.2202del p.Ala736LeufsTer12 frameshift_variant 16/391 NM_000352.6 P4Q09428-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461794
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152104
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingCounsylNov 28, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 05, 2019Variant summary: ABCC8 c.2202delA (p.Ala736LeufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg.c.2506C>T (p.Arg836X), c.3574delG (p.Asp1192fsX16)). The variant was absent in 246134 control chromosomes (gnomAD) but has been reported in the literature in an individual affected with Congenital Hyperinsulinism (Kapoor_2013). This data indicates that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 16, 2023ClinVar contains an entry for this variant (Variation ID: 555310). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 23345197). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala736Leufs*12) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 11, 2023Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36208030, 21989597, 32027066, 18981553, 32792356, 20685672, 27538677, 16613899, 16885549, 18025408, 23345197) -
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 03, 2023- -
Neonatal diabetes mellitus Other:1
Uncertain risk allele, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine ClinicMay 27, 2024This variant is found to be a potent moderate impact, variant with a sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele. -
Maturity onset diabetes mellitus in young Other:1
Uncertain risk allele, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine ClinicMay 27, 2024This variant is found to be a potent moderate impact variant with a sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554924035; hg19: chr11-17448615; API