rs11568364

Variant names:

• chr2-168968473-T-C
• rs11568364
• NM_003742.4:c.2029A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.2029A>G​(p.Met677Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,611,012 control chromosomes in the GnomAD database, including 1,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (626 hom., cov: 32)
  • Exomes 𝑓: 0.020 (799 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0370
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014809668).
• BP6: Variant 2-168968473-T-C is Benign according to our data. Variant chr2-168968473-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 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.2029A>G	p.Met677Val	missense	Exon 17 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.2029A>G	p.Met677Val	missense	Exon 17 of 28	ENSP00000497931.1
	ABCB11	ENST00000858973.1		c.2071A>G	p.Met691Val	missense	Exon 17 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.2029A>G	p.Met677Val	missense	Exon 17 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0579 AC: 8790 AN: 151902 Hom.: 623 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0236 AC: 5830 AN: 246646 AF XY: 0.0213

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0199 AC: 29026 AN: 1458992 Hom.: 799 Cov.: 30 AF XY: 0.0192 AC XY: 13917 AN XY: 725688

African (AFR) AF: 0.179 AC: 5978 AN: 33352

American (AMR) AF: 0.0182 AC: 810 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 359 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.0119 AC: 1021 AN: 85944

European-Finnish (FIN) AF: 0.00345 AC: 184 AN: 53274

Middle Eastern (MID) AF: 0.0445 AC: 256 AN: 5752

European-Non Finnish (NFE) AF: 0.0170 AC: 18833 AN: 1110394

Other (OTH) AF: 0.0263 AC: 1585 AN: 60214

GnomAD4 genome AF: 0.0579 AC: 8808 AN: 152020 Hom.: 626 Cov.: 32 AF XY: 0.0556 AC XY: 4133 AN XY: 74328

African (AFR) AF: 0.164 AC: 6818 AN: 41504

American (AMR) AF: 0.0325 AC: 495 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1237 AN: 67904

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0304 Hom.: 571

Bravo AF: 0.0643

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.163 AC: 618

ESP6500EA AF: 0.0200 AC: 165

ExAC AF: 0.0266 AC: 3216

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0211

EpiControl AF: 0.0214

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Progressive familial intrahepatic cholestasis type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.35
DANN	Benign	0.32
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.065	N
PhyloP100		0.037
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.21
Sift	Benign	0.28	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.14
ClinPred		0.0025	T
GERP RS		-2.0
Varity_R		0.092
gMVP		0.29
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -46

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

Other links and lift over

dbSNP: rs11568364; hg19: chr2-169824983;