NM_003742.4:c.270T>C

Variant names:

• chr2-169013391-A-G
• rs4148777
• NM_003742.4:c.270T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003742.4(ABCB11):​c.270T>C​(p.Phe90Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,613,764 control chromosomes in the GnomAD database, including 1,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (223 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1389 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.723
• Publications: 20 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=-0.64).
• BP6: Variant 2-169013391-A-G is Benign according to our data. Variant chr2-169013391-A-G is described in ClinVar as Benign. ClinVar VariationId is 259151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.723 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 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.270T>C	p.Phe90Phe	synonymous	Exon 5 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.270T>C	p.Phe90Phe	synonymous	Exon 5 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.312T>C	p.Phe104Phe	synonymous	Exon 5 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.270T>C	p.Phe90Phe	synonymous	Exon 5 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7627 AN: 152120 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0354

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0450 AC: 11201 AN: 248894 AF XY: 0.0440

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0751

Gnomad EAS exome AF: 0.0588

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0398 AC: 58202 AN: 1461526 Hom.: 1389 Cov.: 32 AF XY: 0.0394 AC XY: 28675 AN XY: 727050

African (AFR) AF: 0.0697 AC: 2332 AN: 33464

American (AMR) AF: 0.0265 AC: 1185 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 1956 AN: 26130

East Asian (EAS) AF: 0.0636 AC: 2526 AN: 39696

South Asian (SAS) AF: 0.0315 AC: 2717 AN: 86252

European-Finnish (FIN) AF: 0.0976 AC: 5210 AN: 53400

Middle Eastern (MID) AF: 0.0274 AC: 158 AN: 5764

European-Non Finnish (NFE) AF: 0.0354 AC: 39353 AN: 1111756

Other (OTH) AF: 0.0458 AC: 2765 AN: 60364

GnomAD4 genome AF: 0.0502 AC: 7646 AN: 152238 Hom.: 223 Cov.: 32 AF XY: 0.0525 AC XY: 3910 AN XY: 74446

African (AFR) AF: 0.0657 AC: 2729 AN: 41542

American (AMR) AF: 0.0351 AC: 537 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.0619 AC: 320 AN: 5170

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4832

European-Finnish (FIN) AF: 0.106 AC: 1126 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0353 AC: 2404 AN: 68016

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0390 Hom.: 621

Bravo AF: 0.0467

Asia WGS AF: 0.0660 AC: 228 AN: 3476

EpiCase AF: 0.0321

EpiControl AF: 0.0321

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Progressive familial intrahepatic cholestasis type 2 (3)
-	-	2	not provided (2)
-	-	1	Benign recurrent intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.8
DANN	Benign	0.57
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4148777; hg19: chr2-169869901; COSMIC: COSV55587010;