NM_006854.4:c.405A>C

Variant names:

• chr7-6466270-T-G
• rs2230263
• NM_006854.4:c.405A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_006854.4(KDELR2):​c.405A>C​(p.Leu135Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L135L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KDELR2 NM_006854.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.523
• Publications: 22 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=-0.523 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006854.4. 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
	KDELR2	NM_006854.4	MANE Select	c.405A>C	p.Leu135Leu	synonymous	Exon 4 of 5	NP_006845.1	P33947-1
	KDELR2	NM_001100603.2		c.352-3095A>C		intron	N/A	NP_001094073.1	P33947-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDELR2	ENST00000258739.9	TSL:1 MANE Select	c.405A>C	p.Leu135Leu	synonymous	Exon 4 of 5	ENSP00000258739.4	P33947-1
	KDELR2	ENST00000490996.1	TSL:1	c.352-3095A>C		intron	N/A	ENSP00000420501.1	P33947-2
	KDELR2	ENST00000854603.1		c.522A>C	p.Leu174Leu	synonymous	Exon 5 of 6	ENSP00000524662.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 46541

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.6
DANN	Benign	0.77
PhyloP100		-0.52
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230263; hg19: chr7-6505901;