chr7-6446081-T-C

Variant names:

• chr7-6446081-T-C
• NM_139179.4:c.119A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139179.4(DAGLB):​c.119A>G​(p.Tyr40Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,436,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DAGLB NM_139179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

Genes affected

DAGLB (HGNC:28923): (diacylglycerol lipase beta) Enables lipase activity. Involved in arachidonic acid metabolic process. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

KDELR2 (HGNC:6305): (KDEL endoplasmic reticulum protein retention receptor 2) Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells, and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes, and binds the tetrapeptide-containing protein, and returns it to the ER. In yeast, the sorting receptor encoded by a single gene, ERD2, is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. KDELR2 was the second member of the family to be identified, and it encodes a protein which is 83% identical to the KDELR1 gene product. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KDELR2 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta, type 21

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40536106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139179.4. 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
	DAGLB	NM_139179.4	MANE Select	c.119A>G	p.Tyr40Cys	missense	Exon 2 of 15	NP_631918.3	Q8NCG7-1
	DAGLB	NM_001142936.2		c.119A>G	p.Tyr40Cys	missense	Exon 2 of 13	NP_001136408.1	Q8NCG7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAGLB	ENST00000297056.11	TSL:1 MANE Select	c.119A>G	p.Tyr40Cys	missense	Exon 2 of 15	ENSP00000297056.6	Q8NCG7-1
	DAGLB	ENST00000878465.1		c.119A>G	p.Tyr40Cys	missense	Exon 2 of 16	ENSP00000548524.1
	DAGLB	ENST00000878464.1		c.119A>G	p.Tyr40Cys	missense	Exon 2 of 15	ENSP00000548523.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000167 AC: 24 AN: 1436910 Hom.: 0 Cov.: 30 AF XY: 0.0000182 AC XY: 13 AN XY: 714506

African (AFR) AF: 0.00 AC: 0 AN: 31744

American (AMR) AF: 0.00 AC: 0 AN: 37618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 82056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1103146

Other (OTH) AF: 0.0000169 AC: 1 AN: 59226

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.28
Sift	Benign	0.047	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.33		Gain of sheet (P = 0.1208)
MVP		0.73
MPC		0.36
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.23
gMVP		0.77
Mutation Taster		=57/43	polymorphism

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

hg19: chr7-6485712;