rs12968116

Variant names:

• chr18-57655270-C-T
• rs12968116
• NM_001374385.1:c.2855G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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:9
• Conservation: PhyloP100: 5.05
• Publications: 53 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 259820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	NM_001374385.1	MANE Select	c.2855G>A	p.Arg952Gln	missense	Exon 23 of 28	NP_001361314.1	O43520
	ATP8B1	NM_005603.6		c.2855G>A	p.Arg952Gln	missense	Exon 23 of 28	NP_005594.2	O43520
	ATP8B1	NM_001374386.1		c.2705G>A	p.Arg902Gln	missense	Exon 22 of 27	NP_001361315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	ENST00000648908.2	MANE Select	c.2855G>A	p.Arg952Gln	missense	Exon 23 of 28	ENSP00000497896.1	O43520
	ATP8B1-AS1	ENST00000592201.2	TSL:1	n.723-12736C>T		intron	N/A
	ATP8B1	ENST00000857621.1		c.2855G>A	p.Arg952Gln	missense	Exon 23 of 28	ENSP00000527680.1

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

GnomAD2 exomes AF: 0.0824 AC: 20731 AN: 251472 AF XY: 0.0839

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 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

African (AFR) AF: 0.0247 AC: 827 AN: 33480

American (AMR) AF: 0.0435 AC: 1946 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0846 AC: 2212 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0501 AC: 4319 AN: 86256

European-Finnish (FIN) AF: 0.113 AC: 6013 AN: 53414

Middle Eastern (MID) AF: 0.0732 AC: 422 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135441 AN: 1111786

Other (OTH) AF: 0.0985 AC: 5951 AN: 60390

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

African (AFR) AF: 0.0278 AC: 1153 AN: 41532

American (AMR) AF: 0.0652 AC: 997 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0857 AC: 297 AN: 3466

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0535 AC: 258 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10594

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7782 AN: 68012

Other (OTH) AF: 0.0795 AC: 168 AN: 2114

Alfa AF: 0.100 Hom.: 2878

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.12	N
PhyloP100		5.1
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
Vest4		0.17
ClinPred		0.011	T
GERP RS		5.9
Varity_R		0.37
gMVP		0.68
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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