rs2229895

Variant names:

• chr20-10641610-G-A
• rs2229895
• NM_000214.3:c.2766C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10641610-G-A
• chr20-10641610-G-C
• chr20-10641610-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000254958.10(JAG1):​c.2766C>T​(p.Asp922Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,060 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: JAG1 ENST00000254958.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.69
• Publications: 4 publications found

Genes affected

JAG1 (HGNC:6188): (jagged canonical Notch ligand 1) The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]

JAG1 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-10641610-G-A is Benign according to our data. Variant chr20-10641610-G-A is described in ClinVar as Benign. ClinVar VariationId is 213526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000254958.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.2766C>T	p.Asp922Asp	synonymous	Exon 23 of 26	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.2766C>T	p.Asp922Asp	synonymous	Exon 23 of 26	ENSP00000254958.4
	JAG1	ENST00000423891.6	TSL:2	n.2632C>T		non_coding_transcript_exon	Exon 21 of 25
	JAG1	ENST00000617965.2	TSL:5	n.3355C>T		non_coding_transcript_exon	Exon 17 of 17

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2391 AN: 152214 Hom.: 67 Cov.: 33

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00423 AC: 1062 AN: 251148 AF XY: 0.00326

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00190 AC: 2781 AN: 1461728 Hom.: 61 Cov.: 33 AF XY: 0.00166 AC XY: 1204 AN XY: 727190

African (AFR) AF: 0.0580 AC: 1942 AN: 33480

American (AMR) AF: 0.00331 AC: 148 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000409 AC: 455 AN: 1111996

Other (OTH) AF: 0.00315 AC: 190 AN: 60394

GnomAD4 genome AF: 0.0157 AC: 2398 AN: 152332 Hom.: 68 Cov.: 33 AF XY: 0.0152 AC XY: 1131 AN XY: 74496

African (AFR) AF: 0.0536 AC: 2230 AN: 41572

American (AMR) AF: 0.00680 AC: 104 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68028

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00634 Hom.: 10

Bravo AF: 0.0180

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.90
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2229895; hg19: chr20-10622258; COSMIC: COSV105039908;