rs191649793

Variant names:

• chr2-168964250-A-G
• rs191649793
• NM_003742.4:c.2134T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-168964250-A-G
• chr2-168964250-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003742.4(ABCB11):​c.2134T>C​(p.Leu712Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,570,236 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (34 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.377
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-168964250-A-G is Benign according to our data. Variant chr2-168964250-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.377 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00513 (7274/1418400) while in subpopulation MID AF = 0.0121 (69/5690). AF 95% confidence interval is 0.00983. There are 34 homozygotes in GnomAdExome4. There are 3466 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.2134T>C	p.Leu712Leu	synonymous	Exon 18 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.2134T>C	p.Leu712Leu	synonymous	Exon 18 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.2176T>C	p.Leu726Leu	synonymous	Exon 18 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.2134T>C	p.Leu712Leu	synonymous	Exon 18 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 612 AN: 151718 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00823

Gnomad ASJ AF: 0.00780

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00583

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00417 AC: 792 AN: 189988 AF XY: 0.00416

Gnomad AFR exome AF: 0.000872

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00233

Gnomad NFE exome AF: 0.00589

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.00513 AC: 7274 AN: 1418400 Hom.: 34 Cov.: 30 AF XY: 0.00494 AC XY: 3466 AN XY: 701412

African (AFR) AF: 0.000920 AC: 30 AN: 32608

American (AMR) AF: 0.00351 AC: 136 AN: 38700

Ashkenazi Jewish (ASJ) AF: 0.00780 AC: 198 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 37672

South Asian (SAS) AF: 0.00157 AC: 127 AN: 80724

European-Finnish (FIN) AF: 0.00299 AC: 152 AN: 50912

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5690

European-Non Finnish (NFE) AF: 0.00574 AC: 6245 AN: 1087934

Other (OTH) AF: 0.00539 AC: 317 AN: 58784

GnomAD4 genome AF: 0.00403 AC: 612 AN: 151836 Hom.: 5 Cov.: 32 AF XY: 0.00431 AC XY: 320 AN XY: 74196

African (AFR) AF: 0.000771 AC: 32 AN: 41492

American (AMR) AF: 0.00822 AC: 125 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00780 AC: 27 AN: 3462

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00583 AC: 395 AN: 67802

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00565 Hom.: 2

Bravo AF: 0.00414

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Progressive familial intrahepatic cholestasis type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.80
DANN	Benign	0.62
PhyloP100		-0.38
Mutation Taster		=100/0	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: rs191649793; hg19: chr2-169820760;