7-6445973-A-G

Variant names:

• chr7-6445973-A-G
• NM_139179.4:c.227T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139179.4(DAGLB):​c.227T>C​(p.Ile76Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DAGLB NM_139179.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAGLB	NM_139179.4	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 15	ENST00000297056.11	NP_631918.3
DAGLB	NM_001142936.2	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 13		NP_001136408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAGLB	ENST00000297056.11	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 15	1	NM_139179.4	ENSP00000297056.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451138 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;.
Polyphen		0.97	D;.;.;.
Vest4		0.68
MutPred		0.44		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);
MVP		0.90
MPC		0.14
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.44
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-6485604;