2-168923642-T-C

Position:

• chr2-168923642-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003742.4(ABCB11):​c.3946A>G​(p.Thr1316Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.19

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain ABC transporter 2 (size 238) in uniprot entity ABCBB_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003742.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24425861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.3946A>G	p.Thr1316Ala	missense_variant	28/28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.3946A>G	p.Thr1316Ala	missense_variant	28/28		NM_003742.4	ENSP00000497931	P1
ABCB11	ENST00000649448.1	c.2323A>G	p.Thr775Ala	missense_variant	15/15			ENSP00000497165
ABCB11	ENST00000648875.1	c.226+1015A>G		intron_variant				ENSP00000497252
ABCB11	ENST00000439188.1	c.*2344A>G		3_prime_UTR_variant, NMD_transcript_variant	15/15	2		ENSP00000416058

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.18	N;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.51	T;.;.
Sift4G	Benign	0.19	T;.;.
Polyphen		0.82	P;P;.
Vest4		0.52
MutPred		0.25		Loss of glycosylation at T1316 (P = 0.0253);Loss of glycosylation at T1316 (P = 0.0253);.;
MVP		0.85
MPC		0.33
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.86

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: rs1691168576; hg19: chr2-169780152;