2-168968473-T-C

Position:

• chr2-168968473-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/22 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 259145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168968473-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.2029A>G	p.Met677Val	missense_variant	17/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.2029A>G	p.Met677Val	missense_variant	17/28		NM_003742.4	P1
ABCB11	ENST00000649448.1	c.346A>G	p.Met116Val	missense_variant	3/15
ABCB11	ENST00000439188.1	c.*499A>G		3_prime_UTR_variant, NMD_transcript_variant	4/15	2

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

GnomAD3 exomes AF: 0.0236 AC: 5830 AN: 246646 Hom.: 255 AF XY: 0.0213 AC XY: 2853 AN XY: 133764

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 SAS exome AF: 0.0113

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

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0263

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

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0254 Hom.: 189

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial intrahepatic cholestasis type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.38	.;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.065	N;N;.
MutationTaster	Benign	1.0	P
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;B;.
Vest4		0.010
MPC		0.14
ClinPred		0.0025	T
GERP RS		-2.0
Varity_R		0.092
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs11568364; hg19: chr2-169824983;