2-168923626-C-T

Variant names:

• chr2-168923626-C-T
• rs201693189
• NM_003742.4:c.3962G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_003742.4(ABCB11):​c.3962G>A​(p.Ser1321Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,613,782 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1321T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (3 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.18

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 288) in uniprot entity ABCBB_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_003742.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.09623897).
• BP6: Variant 2-168923626-C-T is Benign according to our data. Variant chr2-168923626-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1131495.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.3962G>A	p.Ser1321Asn	missense_variant	Exon 28 of 28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.3962G>A	p.Ser1321Asn	missense_variant	Exon 28 of 28		NM_003742.4	ENSP00000497931.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151966 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 249214 AF XY: 0.000207

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461698 Hom.: 3 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 727134

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00114 AC: 98 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53402

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1111856

Gnomad4 Remaining exome AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152084 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74354

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00146 AC: 0.00145591 AN: 0.00145591

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28733223) -

ABCB11-related disorder Uncertain:1

Jan 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCB11 c.3962G>A variant is predicted to result in the amino acid substitution p.Ser1321Asn. This variant was reported in the heterozygous state in an individual with progressive familial intrahepatic cholestasis (Table S2, Dröge et al. 2017. PubMed ID: 28733223). This variant is reported in 0.12% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Progressive familial intrahepatic cholestasis type 2 Uncertain:1

Apr 21, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.94	L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0070	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.59
MutPred		0.48		Loss of glycosylation at S1321 (P = 0.0309);Loss of glycosylation at S1321 (P = 0.0309);.;
MVP		0.92
MPC		0.61
ClinPred		0.47	T
GERP RS		5.4
Varity_R		0.59
gMVP		0.89
Mutation Taster		=40/60	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201693189; hg19: chr2-169780136;