chr2-168990902-A-G

Variant names:

• chr2-168990902-A-G
• rs2287616
• NM_003742.4:c.807T>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.807T>C​(p.Tyr269Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,022 control chromosomes in the GnomAD database, including 2,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (254 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1827 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.104
• Publications: 21 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=-0.84).
• BP6: Variant 2-168990902-A-G is Benign according to our data. Variant chr2-168990902-A-G is described in ClinVar as Benign. ClinVar VariationId is 259157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.104 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 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.807T>C	p.Tyr269Tyr	synonymous	Exon 9 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.807T>C	p.Tyr269Tyr	synonymous	Exon 9 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.849T>C	p.Tyr283Tyr	synonymous	Exon 9 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.807T>C	p.Tyr269Tyr	synonymous	Exon 9 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 152164 Hom.: 255 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0327 AC: 8111 AN: 248324 AF XY: 0.0282

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.00967

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000881

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0117 AC: 17110 AN: 1460740 Hom.: 1827 Cov.: 31 AF XY: 0.0112 AC XY: 8174 AN XY: 726650

African (AFR) AF: 0.00191 AC: 64 AN: 33424

American (AMR) AF: 0.0529 AC: 2361 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00935 AC: 244 AN: 26088

East Asian (EAS) AF: 0.283 AC: 11237 AN: 39676

South Asian (SAS) AF: 0.0110 AC: 951 AN: 86202

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53372

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.000687 AC: 764 AN: 1111306

Other (OTH) AF: 0.0241 AC: 1455 AN: 60302

GnomAD4 genome AF: 0.0151 AC: 2305 AN: 152282 Hom.: 254 Cov.: 32 AF XY: 0.0163 AC XY: 1214 AN XY: 74450

African (AFR) AF: 0.00385 AC: 160 AN: 41578

American (AMR) AF: 0.0263 AC: 402 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.297 AC: 1534 AN: 5168

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68010

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00829 Hom.: 246

Bravo AF: 0.0199

Asia WGS AF: 0.140 AC: 485 AN: 3476

EpiCase AF: 0.00115

EpiControl AF: 0.000653

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.27
PhyloP100		0.10
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2287616; hg19: chr2-169847412; COSMIC: COSV55591248;