18-57706561-C-T

Position:

chr18-57706561-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

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:6

Conservation

PhyloP100: 5.18

Variant links:

Genes affected

ATP8B1 (HGNC:3706): (ATPase phospholipid transporting 8B1) This gene encodes a member of the P-type cation transport ATPase family, which belongs to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Mutations in this gene may result in progressive familial intrahepatic cholestasis type 1 and in benign recurrent intrahepatic cholestasis. [provided by RefSeq, Jul 2008]

ATP8B1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP8B1. . Trascript score misZ 3.3227 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial intrahepatic cholestasis type 1, cholestasis, intrahepatic, of pregnancy, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.009497732).

BP6

Variant 18-57706561-C-T is Benign according to our data. Variant chr18-57706561-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7271.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=7}. Variant chr18-57706561-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00358 (5237/1461664) while in subpopulation MID AF= 0.0222 (128/5766). AF 95% confidence interval is 0.0191. There are 16 homozygotes in gnomad4_exome. There are 2643 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B1	NM_001374385.1 linkuse as main transcript	c.208G>A	p.Asp70Asn	missense_variant	3/28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2 linkuse as main transcript	c.208G>A	p.Asp70Asn	missense_variant	3/28		NM_001374385.1	ENSP00000497896	P1
	ENST00000588925.5 linkuse as main transcript	n.571-24853C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00319

AC:

800

AN:

251108

Hom.:

AF XY:

0.00324

AC XY:

440

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00210

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00358

AC:

5237

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

2643

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00382

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.00302

AC:

459

AN:

152190

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00314

AC:

381

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP8B1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2018	This variant is associated with the following publications: (PMID: 15888793, 4260417, 28733223, 19731236, 20981092, 15239083, 22995991, 24627769, 24260417, 27884173, 23891399, 32917322) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 â€šÃ„Ã²low-normalâ€šÃ„Ã´ 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. -

Cholestasis, intrahepatic, of pregnancy, 1

Pathogenic:1Uncertain:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Progressive familial intrahepatic cholestasis type 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Benign recurrent intrahepatic cholestasis type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

ATP8B1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.0095

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.94

L;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

N;.

REVEL

Benign

0.23

Sift

Benign

0.26

T;.

Sift4G

Benign

0.28

T;.

Polyphen

1.0

D;D

Vest4

0.39

MVP

0.79

ClinPred

0.036

GERP RS

5.1

Varity_R

0.094

gMVP

0.60

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over