rs73423037
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000352.6(ABCC8):c.2538C>T(p.His846His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,611,952 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0095 ( 23 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 35 hom. )
Consequence
ABCC8
NM_000352.6 synonymous
NM_000352.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0740
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
Variant 11-17412684-G-A is Benign according to our data. Variant chr11-17412684-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157692.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=6}. Variant chr11-17412684-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.074 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00947 (1442/152270) while in subpopulation AFR AF= 0.0321 (1336/41558). AF 95% confidence interval is 0.0307. There are 23 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 SD gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ABCC8 | NM_000352.6 | c.2538C>T | p.His846His | synonymous_variant | 21/39 | ENST00000389817.8 | NP_000343.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ABCC8 | ENST00000389817.8 | c.2538C>T | p.His846His | synonymous_variant | 21/39 | 1 | NM_000352.6 | ENSP00000374467.4 |
Frequencies
GnomAD3 genomes 0.00939 AC: 1429AN: 152152Hom.: 23 Cov.: 32
GnomAD3 genomes
AF:
AC:
1429
AN:
152152
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00257 AC: 636AN: 247026Hom.: 14 AF XY: 0.00201 AC XY: 268AN XY: 133484
GnomAD3 exomes
AF:
AC:
636
AN:
247026
Hom.:
AF XY:
AC XY:
268
AN XY:
133484
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00119 AC: 1737AN: 1459682Hom.: 35 Cov.: 31 AF XY: 0.00102 AC XY: 744AN XY: 725868
GnomAD4 exome
AF:
AC:
1737
AN:
1459682
Hom.:
Cov.:
31
AF XY:
AC XY:
744
AN XY:
725868
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00947 AC: 1442AN: 152270Hom.: 23 Cov.: 32 AF XY: 0.00955 AC XY: 711AN XY: 74454
GnomAD4 genome
AF:
AC:
1442
AN:
152270
Hom.:
Cov.:
32
AF XY:
AC XY:
711
AN XY:
74454
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
12
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 04, 2013 | - - |
Maturity onset diabetes mellitus in young Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs73423037) in MODY yet. - |
Transitory neonatal diabetes mellitus Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs73423037) in neonatal diabetes yet. - |
Diabetes mellitus, transient neonatal, 2 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hyperinsulinemic hypoglycemia, familial, 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Permanent neonatal diabetes mellitus Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at