2-168979878-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003742.4(ABCB11):​c.1185G>A​(p.Glu395Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,578,554 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (66 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-168979878-C-T is Benign according to our data. Variant chr2-168979878-C-T is described in ClinVar as Benign. ClinVar VariationId is 259144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.163 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

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>A	p.Glu395Glu	synonymous	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>A	p.Glu395Glu	synonymous	Exon 11 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.1227G>A	p.Glu409Glu	synonymous	Exon 11 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.1185G>A	p.Glu395Glu	synonymous	Exon 11 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2425 AN: 151028 Hom.: 61 Cov.: 31

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

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: 0.000206

Gnomad OTH AF: 0.00968

GnomAD2 exomes AF: 0.00411 AC: 1021 AN: 248410 AF XY: 0.00286

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00156 AC: 2223 AN: 1427414 Hom.: 66 Cov.: 30 AF XY: 0.00129 AC XY: 918 AN XY: 709630

African (AFR) AF: 0.0548 AC: 1784 AN: 32526

American (AMR) AF: 0.00312 AC: 136 AN: 43622

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

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85636

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

Middle Eastern (MID) AF: 0.00250 AC: 14 AN: 5598

European-Non Finnish (NFE) AF: 0.0000339 AC: 37 AN: 1090154

Other (OTH) AF: 0.00415 AC: 241 AN: 58132

GnomAD4 genome AF: 0.0161 AC: 2429 AN: 151140 Hom.: 61 Cov.: 31 AF XY: 0.0155 AC XY: 1145 AN XY: 73792

African (AFR) AF: 0.0557 AC: 2294 AN: 41172

American (AMR) AF: 0.00660 AC: 100 AN: 15156

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4754

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

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67816

Other (OTH) AF: 0.00958 AC: 20 AN: 2088

Alfa AF: 0.00708 Hom.: 56

Bravo AF: 0.0190

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000548

EpiControl AF: 0.000239

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.6
DANN	Benign	0.40
PhyloP100		0.16
Mutation Taster		=87/13	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: rs57509552; hg19: chr2-169836388;