18-57706561-C-T

Variant names:

• chr18-57706561-C-T
• rs34719006
• NM_001374385.1:c.208G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:6
• Conservation: PhyloP100: 5.18

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]

ENSG00000267787 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in the ATP8B1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Trascript score misZ: 3.3227 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2	c.208G>A	p.Asp70Asn	missense_variant	Exon 3 of 28		NM_001374385.1	ENSP00000497896.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152072 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.00324 AC XY: 440 AN XY: 135720

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.: 16 Cov.: 31 AF XY: 0.00363 AC XY: 2643 AN XY: 727108

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.: 0 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74404

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.: 6

Bravo AF: 0.00292

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jun 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15888793, 4260417, 28733223, 19731236, 20981092, 15239083, 22995991, 24627769, 24260417, 27884173, 23891399, 32917322) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP8B1: BP4, BS1 -

Cholestasis, intrahepatic, of pregnancy, 1 Pathogenic:1 Uncertain:1 Benign:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 1 Uncertain:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign recurrent intrahepatic cholestasis type 1 Uncertain:2

Jul 30, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATP8B1-related disorder Uncertain:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 26, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.94	L;L
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs34719006; hg19: chr18-55373793;