18-57706561-C-T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001374385.1(ATP8B1):c.208G>A(p.Asp70Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00353 in 1,613,854 control chromosomes in the GnomAD database, including 16 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
Consequence
NM_001374385.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP8B1 | NM_001374385.1 | c.208G>A | p.Asp70Asn | missense_variant | Exon 3 of 28 | ENST00000648908.2 | NP_001361314.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00303 AC: 461AN: 152072Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00319 AC: 800AN: 251108Hom.: 2 AF XY: 0.00324 AC XY: 440AN XY: 135720
GnomAD4 exome AF: 0.00358 AC: 5237AN: 1461664Hom.: 16 Cov.: 31 AF XY: 0.00363 AC XY: 2643AN XY: 727108
GnomAD4 genome AF: 0.00302 AC: 459AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00312 AC XY: 232AN XY: 74404
ClinVar
Submissions by phenotype
not provided Benign:4
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ATP8B1: BP4, BS1 -
The ATP8B1 p.D70N variant was identified in the literature in 8 heterozygous individuals with chronic pancreatitis, 3 heterozygous individuals with intrahepatic cholestasis of pregnancy, two compound heterozygous individuals with benign recurrent intrahepatic cholestasis, a heterozygous individual with ‘low-normal’ gamma glutamyl transpeptidase (gGT) cholestasis and two heterozygous individuals with liver injury; this variant was also reported as a heterozygous variant in 9 healthy controls (Mullenbach_2005_PMID:15888793; Klomp_2004_PMID:15239083; Van der Woerd_2013_PMID:24260417; McKay_2013_PMID:24627769; Giovannoni_2015_PMID:26678486; Stolz_2019_PMID:30934130). The variant was identified in dbSNP (ID: rs34719006) and ClinVar (classified as uncertain significance by GeneDx, Illumina, Mendelics and Genomic Research Centre, Shihad Beheshti University of Medical Sciences; as likely benign by EGL Genetic Diagnostics and Invitae; and as pathogenic by OMIM). The variant was identified in control databases in 877 of 282502 chromosomes (2 homozygous) at a frequency of 0.003104, and was observed at the highest frequency in the European (non-Finnish) population in 567 of 129006 chromosomes (freq: 0.004395) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.D70 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In vitro functional analysis reveals that the p.D70N variant does not affect protein localization and has residual activity compared to wildtype (Folmer_2009_PMID:19731236; Takatsu_2014_PMID:25315773). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
This variant is associated with the following publications: (PMID: 15888793, 4260417, 28733223, 19731236, 20981092, 15239083, 22995991, 24627769, 24260417, 27884173, 23891399, 32917322) -
Cholestasis, intrahepatic, of pregnancy, 1 Pathogenic:1Uncertain:1Benign:1
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Progressive familial intrahepatic cholestasis type 1 Uncertain:3
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Benign recurrent intrahepatic cholestasis type 1 Uncertain:2
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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ATP8B1-related disorder Uncertain:1
The ATP8B1 c.208G>A variant is predicted to result in the amino acid substitution p.Asp70Asn. This variant has been reported in benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP) and chronic pancreatitis (CP), but its pathogenicity hasn’t been concluded (Klomp et al. 2004. PubMed ID: 15239083; Müllenbach et al. 2005. PubMed ID: 15888793; van der Woerd et al. 2013. PubMed ID: 24260417). In a functional study, Folmer et al. found that this p.Asp70Asn change didn’t result in a significantly reduced protein expression and it displayed a staining pattern similar to wildtype in a subcellular localization experiment (Folmer et al. 2009. PubMed ID: 19731236). The p.Asp70Asn variant also showed residual interaction with CDC50A, which is required for endoplasmic reticulum (ER) exit and plasma membrane localization. This variant is reported in 0.99% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 2 homozygous individuals. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Progressive familial intrahepatic cholestasis type 2 Uncertain:1
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not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at