18-57691850-T-C

Variant names:

• chr18-57691850-T-C
• rs34315917
• NM_001374385.1:c.1177A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001374385.1(ATP8B1):​c.1177A>G​(p.Ile393Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,120 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I393I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (25 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.85
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010709912).
• BP6: Variant 18-57691850-T-C is Benign according to our data. Variant chr18-57691850-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259815.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00379 (577/152276) while in subpopulation NFE AF = 0.00598 (407/68024). AF 95% confidence interval is 0.0055. There are 2 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B1	NM_001374385.1	c.1177A>G	p.Ile393Val	missense_variant	Exon 12 of 28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2	c.1177A>G	p.Ile393Val	missense_variant	Exon 12 of 28		NM_001374385.1	ENSP00000497896.1

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 152158 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00399 AC: 1003 AN: 251424 AF XY: 0.00398

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00527 AC: 7697 AN: 1461844 Hom.: 25 Cov.: 31 AF XY: 0.00508 AC XY: 3694 AN XY: 727218

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00521 AC: 233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86258

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53420

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00622 AC: 6911 AN: 1111968

Other (OTH) AF: 0.00502 AC: 303 AN: 60394

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152276 Hom.: 2 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74466

African (AFR) AF: 0.00123 AC: 51 AN: 41542

American (AMR) AF: 0.00549 AC: 84 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00598 AC: 407 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00556 Hom.: 12

Bravo AF: 0.00428

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00404 AC: 490

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 28, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP8B1: BS1 -

not specified Benign:4

Feb 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP8B1 c.1177A>G (p.Ile393Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 251424 control chromosomes (gnomAD), predominantly at a frequency of 0.0061 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

May 18, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.0072	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.50	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.27	T;.
Sift4G	Benign	0.44	T;.
Polyphen		0.82	P;P
Vest4		0.20
MVP		0.83
ClinPred		0.017	T
GERP RS		6.1
Varity_R		0.099
gMVP		0.64
Mutation Taster		=69/31	polymorphism

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: rs34315917; hg19: chr18-55359082; COSMIC: COSV99376654; COSMIC: COSV99376654;