NM_003742.4:c.2594C>T

Variant names:

• chr2-168944621-G-A
• rs118109635
• NM_003742.4:c.2594C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003742.4(ABCB11):​c.2594C>T​(p.Ala865Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,605,336 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A865T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 10.0
• Publications: 24 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=0.010960311).
• BP6: Variant 2-168944621-G-A is Benign according to our data. Variant chr2-168944621-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00048 (73/152092) while in subpopulation EAS AF = 0.013 (67/5148). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2594C>T	p.Ala865Val	missense	Exon 21 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.2594C>T	p.Ala865Val	missense	Exon 21 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.2636C>T	p.Ala879Val	missense	Exon 21 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.2489C>T	p.Ala830Val	missense	Exon 20 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 151974 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0130

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00114 AC: 277 AN: 243644 AF XY: 0.00114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000403 AC: 586 AN: 1453244 Hom.: 4 Cov.: 31 AF XY: 0.000475 AC XY: 343 AN XY: 721902

African (AFR) AF: 0.0000302 AC: 1 AN: 33148

American (AMR) AF: 0.0000228 AC: 1 AN: 43836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.0111 AC: 440 AN: 39560

South Asian (SAS) AF: 0.00127 AC: 108 AN: 84860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5718

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1107094

Other (OTH) AF: 0.000350 AC: 21 AN: 59978

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152092 Hom.: 1 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.0130 AC: 67 AN: 5148

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000590 Hom.: 1

Bravo AF: 0.000684

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	ABCB11-related disorder (1)
-	-	1	Progressive familial intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.9	L
PhyloP100		10
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Benign	0.082	T
Sift4G	Benign	0.083	T
Polyphen		0.88	P
Vest4		0.83
MVP		0.94
MPC		0.39
ClinPred		0.14	T
GERP RS		5.7
Varity_R		0.56
gMVP		0.85
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs118109635; hg19: chr2-169801131;