rs12968116

chr18-57655270-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001374385.1(ATP8B1):c.2855G>A(p.Arg952Gln) variant causes a missense change. The variant allele was found at a frequency of 0.105 in 1,613,884 control chromosomes in the GnomAD database, including 9,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (644 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9194 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.05

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]

(HGNC:):

ATP8B1-AS1 (HGNC:56042): (ATP8B1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP8B1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027029812).
• BP6: Variant 18-57655270-C-T is Benign according to our data. Variant chr18-57655270-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-57655270-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.2855G>A	p.Arg952Gln	missense_variant	23/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.683-12736C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.2855G>A	p.Arg952Gln	missense_variant	23/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+13218C>T		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.664-12736C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0794 AC: 12075 AN: 152112 Hom.: 643 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0803

GnomAD3 exomes AF: 0.0824 AC: 20731 AN: 251472 Hom.: 1082 AF XY: 0.0839 AC XY: 11401 AN XY: 135904

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0408

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0469

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.0858

GnomAD4 exome AF: 0.108 AC: 157146 AN: 1461654 Hom.: 9194 Cov.: 33 AF XY: 0.106 AC XY: 77069 AN XY: 727152

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.0435

Gnomad4 ASJ exome AF: 0.0846

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.0985

GnomAD4 genome AF: 0.0793 AC: 12073 AN: 152230 Hom.: 644 Cov.: 32 AF XY: 0.0783 AC XY: 5827 AN XY: 74422

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.0857

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.105 Hom.: 2212

Bravo AF: 0.0748

TwinsUK AF: 0.118 AC: 439

ALSPAC AF: 0.122 AC: 472

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.115 AC: 987

ExAC AF: 0.0854 AC: 10375

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Progressive familial intrahepatic cholestasis type 1 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.12	N;N
MutationTaster	Benign	1.5e-8	P;P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.28	T;.
Sift4G	Benign	0.18	T;.
Polyphen		1.0	D;D
Vest4		0.17
ClinPred		0.011	T
GERP RS		5.9
Varity_R		0.37
gMVP		0.68

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

Other links and lift over

dbSNP: rs12968116; hg19: chr18-55322502; COSMIC: COSV52180891;