18-57695187-GC-AA

Variant names:

• chr18-57695187-GC-AA
• NM_001374385.1:c.923_924delGCinsTT
• ATP8B1 p.Gly308Val

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1_Very_Strong PM1 PM5 PP3

The NM_001374385.1(ATP8B1):​c.923_924delGCinsTT​(p.Gly308Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G308S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• Publications: 0 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: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_001374385.1 (ATP8B1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a topological_domain Cytoplasmic (size 183) in uniprot entity AT8B1_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_001374385.1
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-57695189-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1878254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.923_924delGCinsTT	p.Gly308Val	missense	N/A	NP_001361314.1	O43520
	ATP8B1	NM_005603.6		c.923_924delGCinsTT	p.Gly308Val	missense	N/A	NP_005594.2	O43520
	ATP8B1	NM_001374386.1		c.773_774delGCinsTT	p.Gly258Val	missense	N/A	NP_001361315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B1	ENST00000648908.2	MANE Select	c.923_924delGCinsTT	p.Gly308Val	missense	N/A	ENSP00000497896.1	O43520
	ATP8B1	ENST00000857621.1		c.923_924delGCinsTT	p.Gly308Val	missense	N/A	ENSP00000527680.1
	ATP8B1	ENST00000857625.1		c.923_924delGCinsTT	p.Gly308Val	missense	N/A	ENSP00000527684.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-55362419;