NM_003742.4:c.108T>C

Variant names:

• chr2-169014345-A-G
• rs3815675
• NM_003742.4:c.108T>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.108T>C​(p.Asp36Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,040 control chromosomes in the GnomAD database, including 2,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (245 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1793 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.574
• Publications: 19 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=-0.52).
• BP6: Variant 2-169014345-A-G is Benign according to our data. Variant chr2-169014345-A-G is described in ClinVar as Benign. ClinVar VariationId is 259143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.574 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 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.108T>C	p.Asp36Asp	synonymous	Exon 4 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.108T>C	p.Asp36Asp	synonymous	Exon 4 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.150T>C	p.Asp50Asp	synonymous	Exon 4 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.108T>C	p.Asp36Asp	synonymous	Exon 4 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2263 AN: 152140 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0322 AC: 8013 AN: 248860 AF XY: 0.0277

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.0593

Gnomad ASJ exome AF: 0.00965

Gnomad EAS exome AF: 0.294

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000833

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0115 AC: 16836 AN: 1460782 Hom.: 1793 Cov.: 30 AF XY: 0.0111 AC XY: 8042 AN XY: 726672

African (AFR) AF: 0.00182 AC: 61 AN: 33434

American (AMR) AF: 0.0528 AC: 2361 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00942 AC: 246 AN: 26106

East Asian (EAS) AF: 0.281 AC: 11156 AN: 39636

South Asian (SAS) AF: 0.0105 AC: 906 AN: 86220

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53326

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

European-Non Finnish (NFE) AF: 0.000617 AC: 686 AN: 1111296

Other (OTH) AF: 0.0230 AC: 1386 AN: 60320

GnomAD4 genome AF: 0.0148 AC: 2261 AN: 152258 Hom.: 245 Cov.: 32 AF XY: 0.0159 AC XY: 1183 AN XY: 74432

African (AFR) AF: 0.00363 AC: 151 AN: 41558

American (AMR) AF: 0.0264 AC: 404 AN: 15292

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

East Asian (EAS) AF: 0.292 AC: 1508 AN: 5168

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68012

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00928 Hom.: 299

Bravo AF: 0.0196

Asia WGS AF: 0.134 AC: 465 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Progressive familial intrahepatic cholestasis type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.4
DANN	Benign	0.65
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3815675; hg19: chr2-169870855; COSMIC: COSV55591266;