2-168979878-C-G

Variant names:

• chr2-168979878-C-G
• rs57509552
• NM_003742.4:c.1185G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003742.4(ABCB11):​c.1185G>C​(p.Glu395Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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 Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E395E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.163
• Publications: 3 publications found

Genes affected

ABCB11 (HGNC:42): (ATP binding cassette subfamily B member 11) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]

ABCB11 Gene-Disease associations (from GenCC):

• progressive familial intrahepatic cholestasis type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• benign recurrent intrahepatic cholestasis type 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08288473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003742.4. 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
	ABCB11	NM_003742.4	MANE Select	c.1185G>C	p.Glu395Asp	missense	Exon 11 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.1185G>C	p.Glu395Asp	missense	Exon 11 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.1227G>C	p.Glu409Asp	missense	Exon 11 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.1185G>C	p.Glu395Asp	missense	Exon 11 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427448 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709638

African (AFR) AF: 0.00 AC: 0 AN: 32554

American (AMR) AF: 0.00 AC: 0 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24976

East Asian (EAS) AF: 0.00 AC: 0 AN: 37590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090154

Other (OTH) AF: 0.00 AC: 0 AN: 58136

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151038 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41060

American (AMR) AF: 0.00 AC: 0 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67824

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 56

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.12
Sift	Benign	0.31	T
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.40		Loss of methylation at K400 (P = 0.135)
MVP		0.72
MPC		0.13
ClinPred		0.13	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.82
Mutation Taster		=70/30	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: rs57509552; hg19: chr2-169836388;